KR20230145547A - Anti-pd-l1 antibody treatment of bladder cancer - Google Patents

Abstract

A method of treating bladder cancer (e.g., UC) in a subject having bladder cancer, e.g., urothelial carcinoma (UC), with an effective dose regimen of an anti-PD-L1 antibody, such as durvalumab or an antigen-binding fragment thereof. provided. Also provided are methods in which an anti-PD-L1 antibody is used in combination with another immunotherapeutic agent, such as tremelimumab, to treat bladder cancer, e.g., UC, in a subject having bladder cancer. In some cases, subjects receiving treatment are identified as having bladder cancer or bladder tumors that are PD-L1-low/neg or PD-L1-high. Also provided is a method of using anti-PD-L1 antibody treatment of bladder cancer after standard of care or first-line therapy in a subject who has progressed after standard of care or first-line therapy or has relapsed after neoadjuvant therapy.

Description

Anti-PD-L1 antibody treatment of bladder cancer {ANTI-PD-L1 ANTIBODY TREATMENT OF BLADDER CANCER}

The present invention generally relates to methods of treating bladder cancer in a subject with bladder cancer using effective dose therapy of an anti-PD-L1 antibody, alone or in combination with one or more additional anti-cancer agents or treatments.

Bladder cancer is the 9th most common cancer diagnosis worldwide, with an estimated 429,800 new cases occurring each year, with 165,100 cancer-related deaths reported worldwide in 2012. In the United States, based on medical statistics, 76,690 new cases will be diagnosed and 16,390 deaths will likely occur in 2016. The most common type of cancer of the bladder, ureters, urethra, and urachus is urothelial carcinoma (UC), also known as transitional cell carcinoma (TCC), which accounts for approximately 90% of primary malignancies of the urinary tract. Over 90% of urothelial tumors originate from the bladder, while 8% originate from the renal pelvis and 2% from the ureters and urethra.

Bladder cancer is generally divided into muscle-invasive and muscle-noninvasive diseases based on invasion of the muscle propria. Upon initial diagnosis of bladder cancer, 70% of cases are diagnosed with non-muscle-invasive bladder cancer (NMIBC) and approximately 30% with muscle-invasive bladder cancer (MIBC). Up to 40% of patients with NMIBC develop MIBC within 5 years of diagnosis. Among patients presenting with MIBC at diagnosis, approximately 15% will have locally advanced disease and approximately 8% will have metastatic disease. The prognosis for patients with locally advanced or metastatic UC is poor, with a relative 5-year survival rate of approximately 15%.

Locally advanced or metastatic bladder cancer, especially UC, is a life-threatening disease that requires new and effective treatments, especially in patients whose cancer progresses during or after first line cancer treatment, such as standard-of-care therapy. A great need for options was not met.

Citation or identification of any reference in any section of this application should not be construed as an admission that such reference is available as prior art to the present invention.

Summary of the Invention

As described below, the present invention provides anti-PD-L1 antibodies in effective dose regimens to subjects with cancer of the bladder and/or bladder-related structures, appendages, and tissues, including the ureters, urethra, and urachus. It features an immunotherapy method for treating such cancer by administering. In one embodiment, the bladder cancer is urothelial carcinoma (UC), also known as urothelial carcinoma (UCC) or transitional cell carcinoma (TCC). In some embodiments, the subject has locally advanced UC or metastatic UC. In certain embodiments, the anti-PD-L1 antibody is a human monoclonal antibody that binds PD-L1 and blocks the interaction of PD-L1 with PD-1 and cluster of differentiation (CD) 80 (CD80) (B7.1). It is a ronal antibody (mAb), durvalumab (also referred to herein as MEDI4736). In another embodiment, the anti-PD-L1 antibody is administered with or in combination with another therapeutic or chemotherapeutic agent, such as an anti-CTLA4 antibody (e.g., tremelimumab) or antigen-binding fragment thereof, platinum, etc. It can be administered along with other anti-cancer treatments, such as radiation, surgery, chemotherapy, etc. When reference is made herein to an anti-PD-L1 antibody (e.g., durvalumab) or an anti-CTLA4 antibody (e.g., tremelimumab), such antibody also possesses specific binding to its target antigen. It will be understood that it also includes antigen-binding fragments of antibodies that possess and exhibit specific binding. The use of an effective amount of an anti-PD-L1 antibody in the present method includes primary (1L) treatment for subjects with bladder cancer, such as UC, and standard (SoC) cancer treatment, e.g., treatment containing a platinum drug. It provides both an effective second-line (2L) treatment for subjects with bladder cancer that has progressed after first-line therapy or has relapsed after another treatment regimen.

In one aspect, the methods described herein are suitable for treating a subject with bladder cancer, such as UC, or a bladder tumor, wherein the cancer or tumor cells or tissue derived from the bladder cancer are present at low levels, low levels to negative levels (low levels). /neg), or expressing high levels of PD-L1, e.g., being identified as a PD-L1-low/neg or PD-L1-high cancer or tumor, respectively. Therefore, a method of characterizing a subject's bladder cancer for PD-L1 expression levels effectively determines whether the subject has a tumor that expresses low, low to negative (low/neg), or high levels of PD-L1. Confirmation: using an anti-PD-L1 antibody, such as durvalumab, or combining durvalumab with another therapeutic agent, for example, an anti-CTLA4 antibody, such as tremelimumab, and/or another anticancer agent or therapeutic agent It is possible to instruct the subject on appropriate and effective treatment to be used. By way of example, reduced PD-L1 expression, low PD-L1 expression as well as low/neg PD-L1 expression may be associated with bladder cancer or cancer or tumor cells or tissue derived from a bladder tumor in a subject detected as expressing PD-L1. It refers to about 5% or 5% to about 50%, or about 5% or 5% to about 25%, or about 25%, or 25%. In another example, reduced or low/neg levels of PD-L1 expression have bladder cancer in a subject detected as expressing PD-L1 or staining by a reagent that detects PD-L1, such as an anti-PD-L1 antibody. or about 5% to less than 50%, or about 5% to less than 25%, or about less than 25%, or less than 25% of the cells or tissues derived from a bladder tumor. In certain embodiments, the reduced level or low/neg level of PD-L1 expression results in less than 25% of the cells or tissues derived from bladder cancer, bladder tumor, or bladder tissue in the subject detected as expressing PD-L1. refers to In certain embodiments, high level PD-L1 expression refers to greater than 25% of cells or tissues derived from bladder cancer, bladder tumor, or bladder tissue in a subject detected as expressing PD-L1.

In another aspect, a method of treatment is provided wherein an anti-PD-L1 antibody is administered to a subject with bladder cancer in an amount effective for treating bladder cancer. According to this aspect, the anti-PD-L1 antibody serves as a primary cancer therapy, e.g., as a monotherapy, to treat bladder cancer. In one embodiment, the anti-PD-L1 antibody is durvalumab. In one embodiment, the subject's bladder cancer comprises bladder-related structures and tissues, including the ureters, urethra, urachus, and/or renal pelvis. In one embodiment, the subject's bladder cancer is urothelial carcinoma (UC), advanced UC, or metastatic UC. In one embodiment, the subject is identified as having bladder cancer, e.g., UC, with low/neg PD-L1 expression. In another embodiment, the subject is identified as having bladder cancer, eg, UC, with high PD-L1 expression. In one embodiment, the anti-PD-L1 antibody is administered in combination with another therapeutic or chemotherapeutic agent, such as an anti-CTLA4 antibody (e.g., tremelimumab), platinum, a platinum-containing cancer drug, etc. In one embodiment, durvalumab is administered weekly (Q1W), every 2 weeks (Q2W), every 3 weeks (Q3W), every 4 weeks (Q4W), every 5 weeks (Q5W), every 6 weeks (Q6W), 7 10 mg/kg to 30 mg/kg, or 10 mg/kg to 20 mg/kg, or 10 mg/kg, or 20 mg/kg weekly (Q7W), every 8 weeks (Q8W), or up to every 3 months. Administered in an effective amount. In one embodiment, durvalumab is administered as a treatment for bladder cancer to a subject with bladder cancer, such as UC, in an effective amount of 10 mg/kg Q2W. In another embodiment, durvalumab is administered as a treatment for bladder cancer to a subject with bladder cancer, such as UC, in an effective amount of 10 mg/kg Q4W. In another embodiment, durvalumab is administered as a treatment for bladder cancer to a subject with bladder cancer, such as UC, at an effective amount of 20 mg/kg Q2W. In another embodiment, durvalumab is administered as a treatment for bladder cancer to a subject with bladder cancer, such as UC, at an effective amount of 20 mg/kg Q4W.

In another aspect, a method of treatment is provided wherein an anti-PD-L1 antibody is administered to a subject with bladder cancer, e.g., UC, wherein the subject is receiving a first-line (1L) treatment regimen, e.g., platinum or cisplatin therapy. , or the disease has progressed after platinum drug-containing combination therapy, or a neoadjuvant in which an anti-PD-L1 antibody is administered in an effective amount to treat bladder cancer, or a given period of time after receiving adjuvant therapy, e.g. The subjects had disease recurrence within a year. As will be appreciated by those skilled in the art, adjuvant treatments include anti-cancer or anti-tumor treatments, such as chemicals, to help reduce the risk of cancer or tumor recurrence, for example, after surgery for cancer or tumor. Refers to treatment or radiation therapy. Neoadjuvant therapy refers to the administration of one or more therapeutic agents prior to the main or primary cancer treatment. For example, neoadjuvant hormone therapy may be given before radiation therapy for the treatment of a given cancer or tumor. According to this aspect, the anti-PD-L1 antibody may serve as a second-line cancer therapy to treat bladder cancer after first-line treatment, e.g., platinum drug treatment. In one embodiment, the anti-PD-L1 antibody is durvalumab. In one embodiment, the subject's bladder cancer is UC, including advanced or metastatic UC. In one embodiment, the subject is identified as having bladder cancer, e.g., UC, with negligible PD-L1 expression to low/neg PD-L1 expression. In another embodiment, the subject is identified as having bladder cancer, eg, UC, with high PD-L1 expression. In one embodiment, the anti-PD-L1 antibody is administered in combination with another therapeutic or chemotherapeutic agent, such as an anti-CTLA4 antibody (e.g., tremelimumab), platinum, etc. In one embodiment, durvalumab is administered weekly, every 2 weeks (Q2W), every 3 weeks (Q3W), every 4 weeks (Q4W), every 5 weeks (Q5W), every 6 weeks (Q6W), every 7 weeks ( 10 mg/kg to 50 mg/kg, or 10 mg/kg to 30 mg/kg, or 10 mg/kg to 20 mg/kg, every 8 weeks (Q8W), up to every 6 months, or longer. , or is administered in an effective amount of 10 mg/kg, or 20 mg/kg. In one embodiment, durvalumab is administered as a treatment for bladder cancer to a subject with bladder cancer, such as UC, in an effective amount of 10 mg/kg Q2W. In another embodiment, durvalumab is administered as a treatment for bladder cancer to a subject with bladder cancer, such as UC, in an effective amount of 10 mg/kg Q4W. In another embodiment, durvalumab is administered as a treatment for bladder cancer to a subject with bladder cancer, such as UC, at an effective amount of 20 mg/kg Q2W. In another embodiment, durvalumab is administered to patients with bladder cancer, such as UC, at an effective dose of 20 mg/kg Q4W as a treatment for bladder cancer.

In another aspect, a method of treating bladder cancer, e.g., UC, in a subject having bladder cancer, e.g., UC, wherein the subject has low to negative PD-L1 expression (PD-L1 Provided is a method comprising administering durvalumab to a subject in an amount effective to treat bladder cancer after being identified as -low/neg) or high (PD-L1-high) bladder cancer. In one embodiment, durvalumab is administered in combination with another therapeutic agent, e.g., an immunotherapeutic agent such as an anti-CTLA4 antibody, e.g., tremelimumab or antigen-binding fragment thereof. In one embodiment, durvalumab is administered after the disease has progressed following a first-line (1L) treatment regimen, e.g., platinum or cisplatin therapy, or a combination therapy containing a vaccine drug, or for a given period of time following neoadjuvant or adjuvant therapy, e.g. For example, it is administered as a second-line treatment to subjects whose disease recurs within one year. In one embodiment, durvalumab is administered in an amount of 10 mg/kg Q2W, 10 mg/kg Q4W, 20 mg/kg Q2W, or 20 mg/kg Q4W. In one embodiment, durvalumab is administered by intravenous administration.

In certain embodiments, a method of treatment is provided comprising administering durvalumab in an amount of 10 mg/kg every two weeks (Q2W) to a subject with bladder cancer, e.g., UC. In one embodiment, durvalumab is administered by intravenous (IV) infusion. In one embodiment, the IV infusion occurs over 30 to 90 minutes. In certain embodiments, the IV infusion occurs over 60 minutes. In one embodiment, the subject has UC, locally advanced UC, or metastatic UC. In one embodiment, the subject has locally advanced or metastatic UC that progressed during or after standard (SoC) treatment, e.g., after one standard platinum-based treatment regimen. In one embodiment, 10 mg/kg of durvalumab is administered until a response, e.g., ORR, OS, PFR, or CR, is achieved in the subject, until disease progression, or until unacceptable toxicity is reached. It is administered Q2W over 60 minutes by IV infusion to subjects with locally advanced or metastatic bladder cancer, such as UC.

In another embodiment, a subject with bladder cancer, e.g., UC, is administered durvalumab or an antigen-binding fragment thereof in an amount of about 10 mg/kg to 50 mg/kg, about 1 mg/kg to 10 mg/kg. A method of treatment is provided comprising administering an amount of tremelimumab or an antigen-binding fragment thereof in combination. In one embodiment, the subject is identified as having bladder cancer, e.g., UC, that is low/neg for expression of PD-L1. In one embodiment, durvalumab is administered to the subject at a dose of 10 mg/kg. In one embodiment, durvalumab is administered to the subject every two weeks (Q2W). In one embodiment, durvalumab is administered to the subject at a dose of 10 mg/kg Q2W. In one embodiment, durvalumab is administered to the subject at a dose of 1.5 g. In one embodiment, durvalumab is administered to the subject every 4 weeks (Q4W). In one embodiment, durvalumab is administered to the subject at a dose of 1.5 g Q4W. In one embodiment, durvalumab is administered to the subject via intravenous infusion. In one embodiment, durvalumab is administered to the subject via intravenous infusion over a period of 60 minutes.

In certain embodiments, tremelimumab or an antigen-binding fragment thereof is administered to the subject at a dose of about 1 mg/kg, or at a dose of about 3 mg/kg, or at a dose of about 10 mg/kg. In some embodiments, the subject is administered at least two doses of tremelimumab or an antigen-binding fragment thereof, where the dose is about 1 mg/kg, or about 3 mg/kg, or about 10 mg/kg. In some embodiments, at least two doses are administered about 4 weeks apart or about 12 weeks apart. In other embodiments, the subject is administered at least three doses of tremelimumab or an antigen-binding fragment thereof, where the dose is about 1 mg/kg, or about 3 mg/kg, or about 10 mg/kg. In some embodiments, at least three doses are administered about 4 weeks apart or about 12 weeks apart.

Additionally, a method of treating bladder cancer in a subject having bladder cancer, comprising administering to the subject tremelimumab or an antigen-binding fragment thereof in an amount of 50 to 150 mg every 2 to 4 weeks to treat bladder cancer, comprising: A method is provided in which durvalumab or an antigen-binding fragment thereof is administered to a subject in an amount of 50 to 2000 mg every 2 to 4 weeks (Q2W to Q4W). In one embodiment, durvalumab or an antigen-binding fragment thereof is administered in an amount of 1500 mg every 4 weeks (Q4W), and tremelimumab or an antigen-binding fragment thereof is administered in an amount of 75 mg every 4 weeks (Q4W). . In one embodiment, durvalumab and tremelimumab or their antigen-binding fragments are administered up to four doses per cycle. In certain embodiments, durvalumab and tremelimumab or their antigen-binding fragments are administered simultaneously or at different times. In one embodiment, the subject is identified as having bladder cancer with negligible to low expression of PD-L1 (PD-L1-low/neg). In one embodiment, the subject is identified as having bladder cancer with a high level of PD-L1 expression (PD-L1-high). In embodiments, the bladder cancer is urothelial carcinoma (UC) and/or cancer of bladder-related structures and tissues, including the ureter, urethra, urachus, and/or renal pelvis. In certain embodiments, the bladder cancer is urothelial carcinoma, advanced UC, or metastatic UC.

In various embodiments of any of the above aspects or methods described herein, bladder cancer is cancer of any part of the bladder, for example, the muscle or epithelium as well as the ureters, or urethra, or tubular structures such as the allantoic duct. Bladder cancers that can be treated by the methods described herein include histologically or cytologically confirmed inoperable or metastatic transitional cells of the urothelium (comprising the bladder, ureters, urethra, and renal pelvis) (transitional cells and mixed Also includes carcinoma (including gender transitional cell/non-transitional cell histology). In various embodiments of any of the above aspects or methods described herein, the anti-PD-L1 antibody is durvalumab (MEDI4736). In other embodiments, the anti-CTLA4 antibody that can be co-administered with durvalumab is tremelimumab. In various embodiments of any of the above aspects, the bladder cancer is muscle-invasive or muscle-non-invasive based on invasion by cancer cells of the muscle propria. In certain embodiments of any of the above aspects, the bladder cancer is urothelial carcinoma (UC). In various embodiments of any of the above aspects, the therapeutic agent is administered every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, or every 8 weeks. In various embodiments of any of the above aspects, durvalumab is administered in an amount of 10 mg/kg every 2 weeks or every 4 weeks; It is administered in an amount of 20 mg/kg every 2 weeks, or every 4 weeks, or 1500 mg every 2 weeks, every 3 weeks, or every 4 weeks. In embodiments of any of the above aspects, durvalumab is administered at a dose of 10 mg/kg Q2W or at a dose of 1500 mg Q4W. In one embodiment of any of the above aspects, durvalumab is administered via intravenous infusion.

In various embodiments of any of the above aspects, the subject is responsive to treatment with an anti-PD-L1 antibody, or treatment with an anti-PD-L1 antibody in combination with an anti-CTLA4 antibody or antigen-binding fragment thereof. and achieves disease control (DC) as described herein. In various embodiments of any of the above aspects, PD-L1 expression on bladder cancer cells and tissue is detected using immunohistochemistry (e.g., on formalin-fixed, paraffin-embedded cancer cells). In various embodiments of any of the above aspects, the methods provide an increase in overall survival (OS) (e.g., of weeks, months, or years) compared to application of standard treatments, e.g., platinum-based treatments. increases). In particular, the increase in survival is greater than or greater than about 4 to 6 weeks, 1 to 2 months, 3 to 4 months, 5 to 7 months, 6 to 8 months, or 9 to 12 months. In various embodiments of any of the above aspects, administration of durvalumab is repeated every 2 weeks or about every 2 weeks or every 4 weeks or about every 4 weeks. In various embodiments of any of the above aspects, administration of tremelimumab or antigen-binding fragment thereof is repeated about every four weeks when used in combination with durvalumab.

In various embodiments of any of the above aspects, administration of tremelimumab or antigen-binding fragment thereof is repeated about every 12 weeks. In various embodiments of any of the above aspects, administration of tremelimumab or antigen-binding fragment thereof is administered approximately every 4 weeks for 7 administrations, then every 12 weeks. In various embodiments of any of the above aspects, administration of durvalumab and/or tremelimumab or antigen-binding fragments thereof to a subject in need thereof is by intravenous infusion. In various embodiments of any of the above aspects, durvalumab and an additional anticancer agent or immunotherapeutic agent, such as tremelimumab, are administered simultaneously or at different times. In various embodiments of any of the above aspects, durvalumab and tremelimumab are administered 12 hours, 24 hours, 26 hours, 48 hours, or 72 hours apart; It is administered at 1-, 2-, or 3-week intervals, or at 1-, 2-, and 3-month intervals. In various embodiments of any of the above aspects, the bladder cancer tumor expresses low (reduced) or undetectable (negligible or negative) levels of PD-L1. In various embodiments of any of the above aspects, bladder cancer, e.g., UC, is diagnosed when less than 25% of the cancer or tumor cells in the cancer or tumor cell population express PD-L1 or are treated with a PD-L1 detection agent (e.g. When a detectably labeled anti-PD-L1 antibody (e.g., a detectably labeled anti-PD-L1 antibody) is used, it is low or low/neg for PD-L1 expression when it shows positive staining for PD-L1. In various embodiments of the above aspects, the described treatment methods result in an increase in overall survival, objective response rate, progression free survival, or complete response in the subject. In various embodiments of the above aspects, the median time to treatment response by a subject ranges from about 1 month to 8 months. In various embodiments of the above aspects, the duration of response by the subject is at least 6 months, 9 months, 12 months, or longer. In embodiments of the above methods, treatment response (e.g., overall survival (OS)) is greater than 60% of subjects with high PD-L1 expression on bladder cancer or bladder tumor cells/tissue (e.g., at about 6 months). For example, 68%) are detected; Treatment response (e.g., OS) is detected in more than 40% (e.g., 45%) of subjects with bladder cancer or low/negative PD-L1 expression on bladder tumor cells/tissue at about 6 months. In embodiments of the above methods, treatment response (e.g., overall survival (OS)) is greater than 60% of subjects with high PD-L1 expression on bladder cancer or bladder tumor cells/tissue (e.g., at about 9 months). For example, 65%) is detected; Treatment response (e.g., OS) is detected in more than 35% (e.g., 36%) of subjects with bladder cancer or low/negative PD-L1 expression on bladder tumor cells/tissue at approximately 9 months. In embodiments of the above methods, a treatment response (e.g., overall survival (OS)) is detected in about 60% of subjects with high PD-L1 expression on bladder cancer or bladder tumor cells/tissue at about 12 months, and ; Treatment response (e.g., OS) is detected in about 35% of subjects with bladder cancer or low/negative PD-L1 expression on bladder tumor cells/tissues at about 12 months. In other embodiments of the above methods, about 60% of subjects with UC demonstrate an overall survival (OS) response at about 6 months; More than 55% (eg, 56%) of subjects with UC show an OS response at approximately 9 months; More than 50% (e.g., 52%) of subjects with UC show an OS response at approximately 12 months.

Other features and advantages of the present invention will become apparent from the detailed description and claims.

Figure 1 is a summary of the patient population in the clinical study described herein (Study 1108). In Figure 1 , 1L = first order; 2L+ = second order or higher; DCO = data cut-off date; UC = urothelial carcinoma. DCO date for non-UC patients = April 29, 2016; DCO date for patients in the UC cohort = July 24, 2016. 2L+ post-platinum patients had disease progression during or after platinum-based therapy, including patients whose disease progressed within 12 months of receiving therapy in the neo-adjuvant/adjuvant setting.
Figure 2 shows a blinded independent central review of the UC cohort of Study 1108 (primary efficacy population: treated patients with opportunity for at least 13 weeks of follow-up), as described in Example 2 herein. , Kaplan-Meier analysis of the duration of response as determined by BICR) is shown. In the figure, CI = confidence interval; NR = not reached; NE = not estimable; Prob. = probability; Resp = reaction; UC = urothelial carcinoma.
Figure 3 shows PD-L1 status of patients' tumors in the UC cohort of Study 1108 (primary efficacy population: treated patients with opportunity for follow-up of at least 13 weeks) as determined by independent central blind review (BICR). A bar graph is shown showing the time for the reaction as shown and the duration of the reaction. In the figure, Neg = negative; PD-L1 = programmed cell death ligand-1; UC = urothelial carcinoma.
Figure 4 shows Kaplan showing estimates of overall survival (OS) in the UC cohort (primary efficacy population: treated patients with opportunity for at least 13 weeks of follow-up) of Study 1108 as described in Example 2 herein. -Presents the Meyer plot. The “All” column (c) includes 3 subjects with unknown PD-L1 status and not included in the (a) PD-L1-high or (b) PD-L1-low/neg subgroups. In the figure, CI = confidence interval; NE = not estimable; Neg = negative; NR = not reached; OS = overall survival; UC = urothelial carcinoma.

Justice

Unless otherwise defined, all technical and academic terms used in this specification have meanings commonly understood by those skilled in the art to which the present invention pertains. The following references provide those skilled in the art with general definitions of many terms used in the present invention: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991)]; and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings assigned to them below, unless otherwise specified.

“Anti-PD-L1 antibody” means an antibody that selectively binds to PD-L1 polypeptide. Exemplary anti-PD-L1 antibodies are described, for example, in WO 2011/066389, which is incorporated herein by reference. Durvalumab (MEDI4736) is an exemplary anti-PD-L1 antibody suitable for the methods described herein. Sequences are provided in the sequence listing herein (e.g., SEQ ID NOs. 3-10).

“Low/neg for PD-L1” means a cell or population of cells has a significantly reduced, low, or undetectable (e.g., negative or negligible) level compared to a PD-L1-positive cell or population of cells. This means that PD-L1 is expressed. In one embodiment, PD-L1 expression is on the surface of a tumor, cancer, or immune cell. In one embodiment, the level of PD-L1 is at least about 5%, 10%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, Expression is low/negligible when reduced by 90% or more. In another embodiment, about 5%, 10%, 25%, 30%, 40%, 50%, 60%, 70%, 80% of the cells in the population (e.g., bladder cancer/tumor cells, such as UC cells) Expression is low or negligible (e.g., PD-L-1 low/neg) when less than 90% or more express detectable levels of PD-L1 protein or polynucleotide. In certain embodiments, such as in the context of immunohistochemistry, “low PD-L1” (or PD-L1 low) or “low/neg PD-L1” (or PD-L1-low/neg) refers to cells in a cancer sample. This means that less than about 25% of the cells show staining for PD-L1. In certain embodiments, such as in the context of immunohistochemistry, “low PD-L1” (or PD-L1 low) or “low/neg PD-L1” (or PD-L1-low/neg) is defined as 25% in a cancer sample. This means that less than % of cells show staining for PD-L1. In yet other specific embodiments, the reduced level, low level, or low/neg level of PD-L1 expression means that less than 25% of the cells or tissues are derived from bladder cancer, bladder tumor, or bladder tissue, such as a UC tumor, in the subject. It refers to being. In certain embodiments, high levels of PD-L1 expression include cells or tissues derived from bladder cancer, bladder tumors, or bladder tissue, such as UC tumors, in 25%, 30%, or 25% of subjects detected as expressing PL-L1. It refers to exceeding 40%, 50%, 60%, 70%, 80%, 90%, or more. Cut-off values for high and low or low/neg levels of PD-L1 expression on bladder cancer or bladder tumor cells and/or tissues are known in the art and can be used in various detection and assay procedures practiced in the art. It will be appreciated by skilled practitioners that the In one embodiment, cell sorting analysis, such as immunohistochemistry or staining in conjunction with fluorescence activated cell sorting (FACS), is used.

“PD-L1 polypeptide” means a polypeptide or fragment thereof that has at least about 85% or greater amino acid identity to NCBI Accession No. NP_001254635 (SEQ ID NO:1 below) and has PD-1 and CD80 binding activity. PD-L1 may be used interchangeably with the term “B7-H1”.

PD-L1 polypeptide sequence

NCBI Accession Number NP_001254635

“PD-L1 nucleic acid molecule” means a polynucleotide encoding a PD-L1 polypeptide. An exemplary PD-L1 nucleic acid molecule sequence is provided in NCBI Accession No. NM_001267706 and SEQ ID NO:2 below.

PD-L1 nucleic acid sequence

NCBI accession number NM_001267706 mRNA

“Anti-CTLA4 antibody” means an antibody that selectively binds to CTLA4 polypeptide. Exemplary anti-CTLA4 antibodies include, for example, US Pat. No. 6,682,736; No. 7,109,003; No. 7,123,281; No. 7,411,057; No. 7,824,679; No. 8,143,379; No. 7,807,797; and 8,491,895 (wherein tremelimumab is 11.2.1), which patents are incorporated herein by reference. Tremelimumab is an exemplary anti-CTLA4 antibody. The tremelimumab sequence is provided in the sequence listing below.

As used herein, the term “antibody” refers to an immunoglobulin or fragment or derivative thereof and includes any polypeptide comprising an antigen binding site, whether produced in vitro or in vivo. This term includes, but is not limited to, polyclonal, monoclonal, monospecific, multispecific, non-specific, humanized, single-chain, chimeric, synthetic, recombinant, hybrid, mutant, and graft antibodies. . Unless otherwise modified by the term “intact,” as in “intact antibody,” for the purposes of this disclosure, the term “antibody” refers to an antibody fragment, such as an antigen-binding fragment (Fab), F(ab' ) ₂ , F(ab'), variable domain fragment (Fv), single chain antibody; Single chain variable fragment (scFv), Fd, dAb, single chain antibody, disulfide-linked Fvs (sdFv), intrabody and antigen binding function, i.e. possessing the ability to specifically bind to PD-L1. Also includes other antibody fragments. Typically, such fragments comprise an antigen binding domain, e.g., a PD-L1-binding domain, or one or more fragments from the light and heavy chain variable regions that specifically bind an antigen, e.g., a PD-L1 polypeptide antigen. Contains complementary determining regions (CDRs), such as CDR1, CDR2, and CDR3.

The terms “antigen binding domain”, “antigen binding fragment”, and “binding fragment” refer to the portion of an antibody molecule that contains the amino acids responsible for the specific binding between the antibody and antigen. When the antigen is large, the antigen binding domain can bind only a portion of the antigen. The portion of the antigen molecule responsible for specific interaction with the antigen binding domain is referred to as an “epitope” or “antigenic determinant.” The antigen binding domain typically includes an antibody light chain variable region (V _L ) and an antibody heavy chain variable region (V _H ), but does not necessarily need to include both. For example, the so-called Fd antibody fragment consists only of the V _H domain, but still retains some of the antigen binding function of the intact antibody.

Binding fragments of antibodies are produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies. Binding fragments include Fab, Fab', F(ab')2, Fv, and single-chain antibodies. Antibodies other than “bispecific” or “bifunctional” antibodies are understood to have each of their binding sites identical. Digestion of the antibody by the enzyme papain produces two identical antigen-binding fragments, also known as "Fab" fragments, and an "Fc" fragment, which has no antigen-binding activity but has crystallization ability. Digestion of an antibody by the enzyme pepsin generates an F(ab') ₂ fragment in which the two arms of the antibody molecule remain connected and contains two antigen binding sites. The F(ab') ₂ fragment has the ability to cross-link antigen. As used herein, “Fv” refers to the minimal fragment of an antibody that possesses both an antigen recognition site and an antigen binding site. As used herein, “Fab” refers to a fragment of an antibody comprising the constant domain of the light chain and the CHI domain of the heavy chain.

The term “mAb” refers to a monoclonal antibody. Antibodies of the present invention include, but are not limited to, intact natural antibodies, bispecific antibodies; chimeric antibodies; Includes Fab, Fab', single chain V region fragments (scFv), fusion polypeptides, and atypical antibodies.

“Biological sample” means any tissue, cell, fluid, or other material derived from an organism. In one embodiment, the biological sample is a bladder cancer or UC tumor biopsy sample.

As used herein, “biomarker” or “marker” generally refers to a protein, nucleic acid molecule, clinical indicator, or other analyte that is associated with a disease. In one embodiment, the marker is differentially present in a biological sample obtained from a subject with the disease (e.g., bladder cancer) compared to the level present in a control sample or reference.

In this disclosure, “comprise,” “including,” “containing,” and “having,” etc. may have the meanings assigned thereto in U.S. patent law, and may mean “including,” “including,” etc. There is; “Consisting essentially of” or “consisting essentially of” likewise has the meaning ascribed to it in United States patent law, and these terms are open-ended, unless the basic or novel characteristics of the thing referred to are altered by the presence of more than the thing referred to. It allows for the existence of more than what has been said, but excludes prior art implementations.

As used herein, the terms “determination,” “evaluation,” “assay,” “measurement,” and “detection,” and “identification” refer to both quantitative and qualitative determinations and, accordingly, “ The term “determination” is used interchangeably herein with “assay,” “measurement,” etc. When a quantitative determination is intended, the phrase “determine the quantity” of an analyte, substance, protein, etc. is used. When qualitative and/or quantitative determinations are intended, the phrases “determine the level” of an analyte or “detect” an analyte are used.

“Disease” means any disease or disorder that impairs, interferes with, or disrupts the normal function of a cell, tissue, or organ. In diseases such as cancer (eg, bladder cancer), the normal function of cells, tissues or organs is disrupted to allow immune evasion and/or escape. As mentioned above, bladder cancer includes cancer of any part of the bladder, such as the muscle or epithelium, as well as tubular structures such as the ureters, or urethra, or the urachus. Bladder cancer can be muscle-invasive or muscle-noninvasive based on invasion by cancer cells of the muscle propria.

The terms “isolated,” “purified,” or “biologically pure” refer to a substance that does not contain varying degrees of normally accompanying constituents as found in nature. “Isolation” means a degree of separation from the original source or surroundings. “Purification” means a degree of separation higher than isolation. A “purified” or “biologically pure” protein does not contain sufficient other substances such that any impurities will not substantially affect the biological properties of the protein or cause other deleterious consequences. That is, a nucleic acid or peptide is substantially free of cellular material, viral material, or culture medium when produced by recombinant DNA techniques or substantially free of chemical precursors or other chemicals when synthesized chemically. Purified as used in the specification. Purity and homogeneity are typically determined using analytical chemistry techniques, such as polyacrylamide gel electrophoresis, high performance liquid chromatography (HPLC), mass spectrometry analysis, etc. The term “purified” can mean that the nucleic acid or protein gives rise to essentially one band in an electrophoresis gel. For proteins that can be modified, for example, phosphorylated or glycosylated, various modifications can result in a variety of isolated proteins that can be individually purified.

“Reference” means a standard of comparison.

“Responsiveness” in the context of therapy means sensitivity to treatment.

“Specifically binds” means a compound that recognizes and binds to a specific molecule (e.g., a polypeptide) but does not substantially recognize and bind to other molecules in the sample, e.g., a biological sample (e.g., an antibody). ) means. For example, two molecules that bind specifically form a complex that is relatively stable under physiological conditions. Specific binding is generally characterized by high affinity and low to medium capacity, as distinguished from non-specific binding, which has low affinity and medium to high capacity. Typically, binding is considered specific when the affinity constant K _A is higher than 10 ⁶ M ^-1 , more preferably higher than 10 ⁸ M ^-1 . If desired, non-specific binding can be reduced without substantially affecting specific binding by varying the binding conditions. Appropriate binding conditions, such as concentration of antibody, ionic strength of the solution, temperature, time allowed for binding, concentration of blocking agent (e.g., serum albumin, milk casein), etc., can be optimized by one skilled in the art using routine techniques. .

“Subject” means a human, such as a human patient, a non-human primate, or a mammal, including, but not limited to, a non-human mammal, such as a canine, horse, canine, sheep, or feline.

Ranges provided herein are understood as shorthand for all values within the range, including the first and last specified values. For example, the range from 1 to 50 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, It is understood to include any number, combination of numbers, or subrange from the group consisting of 46, 47, 48, 49, or 50.

As used herein, the terms “treat,” “treating,” “treatment,” and the like refer to reducing, reducing, attenuating, alleviating, inhibiting, or ameliorating a disorder and/or symptoms associated therewith. . Although not excluded, it will be appreciated that treating a disorder or disease does not require complete elimination of the disorder, disease or symptoms associated therewith.

Unless specifically stated or obvious from the context, the term “or” as used herein is understood to be inclusive. Unless specifically stated or obvious from the context, as used herein, terms in the singular form are understood to refer to the singular and the plural.

Unless specifically stated or obvious from the context, as used herein, the term “about” is understood to be within a range commonly accepted in the art, e.g., within two standard deviations of the mean. The term “about” means 5%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.05%, or 0.01% of the stated value. It is understood to refer to within. Unless otherwise clear from the context, all numerical values given herein are modified by the term about.

Reference to a list of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of the listed groups. Reference to an embodiment of a variable or aspect herein includes that embodiment as any single embodiment or that embodiment in combination with any other embodiment or portion thereof.

Any composition or method provided herein can be combined with one or more of any other compositions and methods provided herein.

DETAILED DESCRIPTION OF THE INVENTION

As described below, the present invention relates to subjects with bladder cancer and/or cancers or tumors expressing varying levels of PD-L1, such as tumors with low/negligible PD-L1, or tumors with high PD-L1. In a subject identified, a method of treating bladder cancer, e.g., urothelial carcinoma (UC), with an anti-PD-L1 antibody, particularly durvalumab, is featured. The methods of treating bladder cancer described herein include treating bladder cancer in a subject by administering an effective amount of an anti-PD-L1 antibody as a primary cancer treatment. The treatment methods described herein are provided to a subject with bladder cancer after the subject has been treated with a primary cancer therapy, such as a standard (SoC) therapy, e.g., a platinum-containing drug, but the disease has progressed or relapsed after the primary SoC therapy. It may also include administering an effective amount of an anti-PD-L1 antibody. In certain embodiments, the anti-PD-L1 antibody is durvalumab (MEDI4736). In embodiments, the anti-PD-L1 antibody is co-administered simultaneously or sequentially with an effective amount of another cancer therapeutic or immunotherapeutic agent, e.g., an anti-CTLA4 antibody such as tremelimumab, or antigen-binding fragment thereof.

PD-L1

The role of the immune system in tumor control, particularly T cell-mediated cytotoxicity, is well recognized. There is growing evidence that T cells control tumor growth and survival in cancer patients, both in early and late stages of the disease. However, tumor-specific T cell responses are difficult to increase and sustain in cancer patients.

Two important T cell regulatory pathways in immune cell function are through the programmed death ligand 1 (PD-L1, also known as B7H-1 or CD274) protein and the cytotoxic T lymphocyte antigen-4 (CTLA-4, CD152) protein. transmit signals.

PD-L1 is part of a complex system of immunomodulatory receptors and ligands involved in controlling T cell activation. PD-L1 protein is a member of the B7 ligand family that inhibits T cell activity by binding to the PD-1 receptor and CD80. In normal tissues, PD-L1 is expressed on T cells, B cells, dendritic cells, macrophages, mesenchymal stem cells, bone marrow-derived mast cells, as well as various non-hematopoietic cells. Its normal function involves T cell activation and activation through interaction with its two receptor proteins, programmed death 1 (also known as PD-1 or CD279) and CD80 (also known as B7-1 or B7). It is about regulating the balance between tolerance.

PD-L1 is also expressed by tumors and acts at multiple sites to help tumors evade detection and elimination by the host immune system. PD-L1 is expressed at high frequency in a wide range of cancers. Expression of PD-L1 on both tumor cells (TC) and tumor-infiltrating immune cells (IC) is induced by inflammatory signals typically associated with adaptive immune responses (e.g., IFNγ production). Binding of PD-L1 to PD-1 on activated T cells protects the tumor from immune elimination by transmitting an inhibitory signal to the T cells. PD-L1 can also inhibit T cell activation through binding to CD80, but the exact mechanism is under investigation. In some cancers, expression of PD-L1 has been associated with reduced survival and adverse prognosis. Antibodies that block the interaction between PD-L1 and its receptor can alleviate PD-L1-dependent immunosuppressive effects and enhance the cytotoxic activity of antitumor T cells in vitro. Additionally, in vitro studies revealed that durvalumab inhibits tumor growth in a xenograft model through a T cell-dependent mechanism. Without being bound by theory, in the methods of the invention durvalumab stimulates the anti-tumor immune response in a subject with bladder cancer by binding to PD-L1 and shifting the balance toward the anti-tumor response.

CTLA4

In contrast to PD-L1, cytotoxic T-lymphocyte-related antigen-4 (CTLA-4) is constitutively expressed by regulatory T cells and is upregulated on activated T cells. CTLA4 acts as a corepressor that blocks T cell responses after CD28-mediated T cell activation. After T cell receptor (TCR) binding, CTLA4 regulates the magnitude of early activation of naive and memory T cells and is believed to be part of a central inhibitory pathway that influences both antitumor immunity and autoimmunity. CTLA4 is expressed primarily on T cells, and expression of its ligands, CD80 (B7.1) and CD86 (B7.2), is largely restricted to antigen presenting cells, T cells, and other immune mediator cells. Binding of CTLA-4 to CD80 or CD86 on tumor infiltrating immune cells (IC) results in inhibition of T cell activation. Antagonistic anti-CTLA4 antibodies that block the CTLA4 signaling pathway have been reported to enhance T cell activation. One such antibody, ipilimumab, was approved by the FDA in 2011 for the treatment of metastatic melanoma. Another anti-CTLA4 antibody, tremelimumab, was tested in a phase 3 clinical trial for the treatment of advanced melanoma, but did not significantly increase the overall survival of patients compared to the standards at the time (temozolomide or dacarbazine). I couldn't do it.

anti-PD-L1 antibody

Antibodies that specifically bind to PD-L1 and inhibit PD-L1 activity (e.g., bind PD-1 and/or CD80) are useful in the treatment of bladder cancer (e.g., UC).

An exemplary anti-PD-L1 antibody, durvalumab (MEDI4736), is a human monoclonal antibody (mAb) (immunoglobulin G1 (IgG1) kappa) genetically engineered to reduce antibody-dependent cell-mediated cytotoxicity (ADCD). )am. Durvalumab binds to PD-L1 and blocks the interaction of PD-L1 with the PD-1 receptor on T cells and the cluster of differentiation (CD80, B7.1) receptor on tumor-infiltrating immune cells (ICs). Durvalumab alleviates PD-L1-mediated inhibition of human T cell activation in vitro by antagonizing the inhibitory effect of PD-L1 on primary human T cells, resulting in restored proliferation of primary human T cells and interferon gamma (IFNγ) and can inhibit tumor growth in xenograft models through a T cell-dependent mechanism.

Information regarding durvalumab (or fragments thereof) for use in the methods provided herein can be found in U.S. Pat. No. 8,779,108, the disclosure of which is incorporated herein by reference in its entirety. The crystallizable fragment (Fc) domain of durvalumab contains a triple mutation of the IgG1 heavy chain that reduces binding to Fcγ receptors and the complement component C1q, which are responsible for mediating antibody-dependent cell-mediated cytotoxicity (ADCC). Contained in the constant area.

Durvalumab (MEDI4736) and antigen-binding fragments thereof for use in the methods provided herein comprise heavy and light chains or heavy and light chain variable regions. In certain embodiments, durvalumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:3 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4. Includes area. In certain embodiments, durvalumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region is the Kabat sequence of SEQ ID NO:5-7. ) and the light chain variable region comprises the Kabat defined CDR1, CDR2, and CDR3 sequences of SEQ ID NO:8 to 10. Those skilled in the art will readily be able to identify Chothia defined, Abm defined, Kabat defined, or other CDR definitions known to those skilled in the art. In certain embodiments, durvalumab or an antigen-binding fragment thereof for use in the methods provided herein comprises the variable heavy and variable light chains of the 2.14H9OPT antibody as disclosed in WO 2011/066389 A1, the entire contents of which are incorporated herein by reference. Contains CDR sequences.

The methods of treating bladder cancer described herein are particularly effective in subjects with bladder cancer, or UC. The method involves determining whether bladder cancer or bladder tumor cells or tissue, including UC cells or tissue, express low levels of PD-L1 (PD-L1-low) or negative/low levels of PD-L1 (PD-L1-low/neg). It is also effective in treating subjects found to have. The methods herein can also be used to treat bladder cancer, e.g., UC, in a subject with a bladder cancer (e.g., UC) tumor that expresses high levels of PD-L1 (e.g., a tumor with high PD-L1). It is effective in doing so.

Currently available treatments for advanced or metastatic urothelial carcinoma (UC) and their associated disadvantages

Initial treatment for locally advanced disease

Locally advanced UC is commonly treated by radical cystectomy and neoadjuvant and adjuvant chemotherapy. Systemic combination chemotherapy with platinum agonists is the regimen of choice in both neoadjuvant and adjuvant settings. Patients whose disease recurs 12 months after neoadjuvant or adjuvant therapy may be retreated with platinum-based therapy as first-line (1L) therapy as described below, but disease relapses within 1 year of treatment in approximately 25% of patients. This happens again. These patients are not eligible for standard platinum-based therapies and have limited treatment options.

First-line platinum-based therapy for locally advanced or metastatic disease

For patients with locally advanced or metastatic UC, cisplatin-containing combination chemotherapy, introduced nearly 30 years ago, is the current standard (SoC). First-line (1L) chemotherapy includes cisplatin/gemcitabine or methotrexate, vinblastine, ADRIAMYCIN ^™ (doxorubicin), and cisplatin (MVAC). This treatment regimen resulted in an objective response rate (ORR) of 46% to 60%, a median progression-free survival (PFS) of 7 to 8 months, and a median overall survival (OS) of 13 to 15 months in a 1L treatment regimen. brought it However, approximately half of patients are unsuitable for cisplatin-containing chemotherapy due to poor performance status, renal dysfunction, or comorbidities, and such patients are typically treated with carboplatin-based therapy or single-agent taxane or Palliative treatment with gemcitabine is given. This treatment is less effective than cisplatin-based chemotherapy, with an objective response rate (ORR) of approximately 30% to 40%; Median PFS of approximately 3 to 6 months; and rarely results in a median OS exceeding 10 months.

Treatment after platinum treatment

Despite the clinical benefit in the 1L setting, disease progression invariably occurs in patients after discontinuation of chemotherapy, even in patients initially responding to chemotherapy. Each year, approximately 6,500 patients in the United States undergo second-line treatment (2L) for locally advanced or metastatic UC.

Currently, there are no available or standard treatments in the United States for patients whose disease has progressed after 1L therapy or whose disease has relapsed within 1 year of neoadjuvant or adjuvant therapy. In Europe, based on a randomized phase 3 trial comparing vinflunine plus best supportive care (BSC) versus BSC alone in patients with UC whose disease progressed after 1L platinum-containing chemotherapy. Therefore, vinflunine was approved for 2L therapy. However, this trial did not meet its primary OS endpoint. Post hoc multivariate Cox analysis adjusting for prognostic factors revealed a 23% reduction in the risk of death in patients treated with vinflunine plus BSC compared with those treated with BSC alone (hazard ratio [HR] = 0.77 [95% CI: 0.61; 0.98]; p = 0.036). In the eligible population, median OS was longer in patients treated with vinflunine + BSC than in patients treated with BSC (6.9 months vs. 4.3 months, respectively; HR = 0.78 [95% CI: 0.61, 0.99], p = 0.040 ). Improved ORR (8.6% vs. 0%, 95% CI: 5.0%, = 13.7%; p = 0.006) and median PFS (3.0 months vs. 1.5 months; p = 0.001) were observed in the evaluable patient population. In the trial, the median duration of response (DoR) to vinflunine therapy was 7.4 months.

In the United States, post-platinum therapy includes off-label use of taxanes (docetaxel, paclitaxel, nab-paclitaxel) or a combination of paclitaxel and gemcitabine. Evidence supporting the use of these agents comes primarily from small, uncontrolled phase 2 clinical trials, with highly variable results dependent on patient selection. Analysis of frequently used second-line (2L) treatment with single-agent cytotoxic chemotherapy showed an ORR of approximately 10% and no improvement in OS. A meta-analysis of 2L single-agent and doublet chemotherapy regimens, including cisplatin or carboplatin, showed an improvement in ORR with doublet chemotherapy (14.2% vs. 31.9%, respectively) and median PFS (2.7 months each). There was a moderate difference in median OS (7.0 months vs. 8.5 months) or median OS (7.0 months vs. 8.5 months). Data pooled from 10 phase 2 trials evaluating 2L chemotherapy, biologics, and combination therapy using chemotherapy and biologics showed an OS rate of 20% (95% CI: 17, 24) at 12 months. .

These chemotherapy regimens are palliative and have significant adverse reactions that can lead to treatment intolerance. Reported grade 3 or 4 toxicities include, but are not limited to, neutropenia, anemia, fatigue, constipation, and thrombocytopenia. Locally advanced or metastatic UC in patients who have previously received platinum-based therapy is a serious and life-threatening disease, and new treatments and treatment regimens are urgently needed. The present methods provide such necessary treatments and treatment regimens for patients with UC, advanced UC, or metastatic UC.

Anti-PD-L1 (durvalumab) monotherapy or combination therapy for the treatment of bladder cancer, e.g., UC

The methods described herein include the administration of an effective amount of an anti-PD-L1 antibody, such as durvalumab, to a subject in need of treatment having bladder cancer, e.g., UC. Provides related medical and clinical benefits. The therapeutic benefits of anti-PD-L1 antibodies, particularly durvalumab, as monotherapy or first-line (1L) treatment for bladder cancer, such as UC, are described herein and demonstrated in the examples.

For example, locally advanced or metastatic urothelial carcinoma ( There are currently no available treatments or standard treatments in the United States for patients with UC. Chemotherapy after platinum treatment is generally palliative and has limited clinical effectiveness and significant adverse reactions. Locally advanced or metastatic UC is a life-threatening disease and there is a great unmet need for new treatment options in patients whose disease progresses during or after treatment involving platinum-containing chemotherapy drug regimens.

Therefore, to address this need, the present method treats subjects with bladder cancer, such as UC, and determines that the cancer is cured within 1 year after first-line (1L) anticancer treatment, such as treatment with platinum-containing chemotherapy drugs or drug therapy. Provides effective therapeutic benefits associated with the use of anti-PD-L1 antibodies, particularly durvalumab, for treating subjects with relapsed or advanced bladder cancer, e.g., UC.

In all embodiments of the methods described herein, the subject undergoing or to be treated according to the methods is identified as having bladder cancer, particularly UC, with varying levels of PD-L1 expression. In some embodiments, the cancer or tumor cells or tissue of a subject with bladder cancer, particularly UC, have negative to low levels of PD-L1 (PD-L1-low/neg), or high levels of PD-L1 (PD-L1). -high). According to the present invention, a therapeutic method comprising an anti-PD-L1 antibody, in particular durvalumab, for the treatment of bladder cancer, in particular UC, provides to a subject in need thereof, wherein the cancer or tumor has PD-L1 expression. -If confirmed to be L1-low/neg or PD-L1-high, comprising administering an effective amount of an anti-PD-L1 antibody, particularly durvalumab, to treat bladder cancer, e.g., UC, in the subject. do. In one embodiment, cancer or tumor cells or tissue are considered PD-L1low/neg when PD-L1 expression is less than 25% compared to a suitable control, for example, as measured by immunohistochemistry or staining assay. It is considered. In one embodiment, cancer or tumor cells or tissue are considered PD-L1-high when PD-L1 expression is greater than 25% compared to a suitable control, for example, as measured by immunohistochemistry or staining assays. It is considered. Expression of PD-L1 on cancer or tumor cells and tissues determined to express PD-L1 at PD-L1-low/neg or PD-L1-high levels relative to control levels, as recognized by the skilled practitioner. The cutoff value for depends on the type of assay or assays used to determine PD-L1 expression, and such assays can be readily performed by those skilled in the art.

In embodiments of all of the above methods, the anti-PD-L1 antibody is administered weekly, every 2 weeks (Q2W), every 3 weeks (Q3W), every 4 weeks (Q4W), every 5 weeks (Q5W), or every 6 weeks ( 1 mg/kg to 50 mg/kg, or about 4 mg/kg to 5 mg/kg, or 5 mg/kg (Q6W), every 7 weeks (Q7W), every 8 weeks (Q8W), up to 6 months, or longer. mg/kg to 10 mg/kg, or 10 mg/kg to 50 mg/kg, or 10 mg/kg to 30 mg/kg, or 10 mg/kg to 20 mg/kg, or 10 mg/kg, or 20 Durvalumab administered in an effective amount (or effective dose) of mg/kg, or 1500 mg. In certain embodiments, durvalumab is administered as a treatment for bladder cancer (or UC) at an effective amount of 10 mg/kg Q2W to a subject with bladder cancer, such as UC. In certain embodiments, durvalumab is administered as a treatment for bladder cancer (or UC) at an effective amount of 10 mg/kg Q4W to a subject with bladder cancer, such as UC. In certain embodiments, durvalumab is administered as a treatment for bladder cancer (or UC) at an effective amount of 20 mg/kg Q2W to a subject with bladder cancer, such as UC. In certain embodiments, durvalumab is administered as a treatment for bladder cancer (or UC) at an effective amount of 20 mg/kg Q4W to a subject with bladder cancer, such as UC. In certain embodiments, durvalumab is administered as a treatment for bladder cancer (or UC) in an effective amount of 1.5 g Q2W to a subject with bladder cancer, such as UC. In certain embodiments, durvalumab is administered as a treatment for bladder cancer (or UC) in an effective amount of 1.5 g Q4W to a subject with bladder cancer, such as UC. In another embodiment, the anti-PD-L1 antibody, e.g., durvalumab, is administered intravenously, such as via intravenous (IV) infusion. In one embodiment, the IV infusion is administered with the anti-PD-L1 antibody over a predetermined period of time, such as 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, or 90 minutes. For example, it delivers durvalumab. In certain embodiments, the IV infusion delivers a dose of an anti-PD-L1 antibody, e.g., durvalumab, over 60 minutes. In related embodiments, an anti-PD-L1 antibody, e.g., durvalumab, is administered to an endpoint, e.g., when the subject reaches an overall or complete response, or overall survival, disease progression, or unacceptable toxicity. administered until. Such endpoints can be determined by an experienced medical practitioner or clinician.

In another embodiment, the anti-PDL-L1 antibody (e.g., durvalumab) is administered in combination with another therapeutic agent, immunotherapeutic agent, or chemotherapeutic agent, such as an anti-CTLA4 antibody (e.g., tremelimumab). do. In some embodiments, standard drugs, such as platinum chemotherapeutics, platinum-containing chemotherapeutics, etc., are also administered along with anti-PD-L1 and/or anti-CTLA4 antibodies or antigen-binding fragments thereof. In this combination therapy, the antibodies may be administered separately or together at the same time or at different times. Additionally, standard medications can be administered simultaneously with or at a different time than the administration of the anti-PD-L1 antibody and/or anti-CTLA4 antibody.

Anti-PD-L1 and anti-CTLA4 (tremelimumab) treatment

Subjects suffering from bladder cancer (e.g., UC) can be tested for PD-L1 polynucleotide or polypeptide expression in the process of selecting a treatment method. Have tumors expressing negligible or low PD-L1 (e.g., as defined by Ct or IHC-M score) or have reduced (low) or undetectable levels of PD-L1 compared to baseline levels Subjects identified as having are confirmed to be responsive to treatment with an anti-PD-L1 antibody, such as durvalumab, or a combination of an anti-PDL-L1 antibody and an anti-CTLA4 antibody, such as tremelimumab. . Such subjects are administered an anti-PD-L1 antibody or antigen-binding fragment thereof, such as durvalumab in combination with tremelimumab.

Information regarding tremelimumab (or antigen-binding fragments thereof) for use in the methods provided herein can be found in U.S. Pat. No. 6,682,736, wherein tremelimumab is referred to as 11.2.1, The disclosure of the patent is incorporated herein by reference in its entirety. Tremelimumab (also known as CP-675,206, CP-675, CP-675206, and ticilimumab) is highly selective for CTLA4 and inhibits CD80 (B7.1) and CD86 (B7.2). It is a human IgG ₂ monoclonal antibody that blocks the binding of CTLA4. Tremelimumab has been shown to cause immune activation in vitro, and some patients treated with tremelimumab have shown tumor regression.

Tremelimumab for use in the methods provided herein comprises a heavy chain and a light chain, or a heavy chain variable region and a light chain variable region. In certain embodiments, tremelimumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:11 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:11. Includes area. In certain embodiments, tremelimumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the Kabat-defined sequence of SEQ ID NO:13-15. The light chain variable region comprises the Kabat defined CDR1, CDR2, and CDR3 sequences of SEQ ID NO:16-18. Those skilled in the art will readily be able to identify Chothia-defined, Abm-defined, Kabat-defined, or other CDR definitions known to those skilled in the art. In certain embodiments, tremelimumab or an antigen-binding fragment thereof for use in the methods provided herein comprises the variable heavy and variable heavy chains of the 11.2.1 antibody as disclosed in U.S. Pat. No. 6,682,736, the entire contents of which are incorporated herein by reference. Contains light chain CDR sequences.

In certain embodiments, subjects shown to have bladder cancer, i.e., UC, are administered durvalumab or an antigen-binding fragment thereof and tremelimumab or an antigen-binding fragment thereof. Durvalumab or antigen-binding fragments thereof and tremelimumab or antigen-binding fragments thereof can be administered once or infrequently and still provide benefit to patients. In a further embodiment, additional subsequent doses are administered to the subject. Subsequent doses may be administered at various time intervals depending on the subject's age, weight, clinical evaluation, tumor burden, and/or other factors, including the judgment of the attending physician, clinician, or medical practitioner.

The interval between doses of durvalumab or antigen-binding fragment thereof may be every 2 weeks (Q2W), every 3 weeks (Q3W), or every 4 weeks (Q4W). The interval between doses of tremelimumab or antigen-binding fragment thereof may be every 4 weeks. The interval between doses of tremelimumab or antigen-binding fragment thereof may be every 2 weeks, every 3 weeks, every 4 weeks, etc., up to every 12 weeks, up to a maximum of 4 doses per cycle. In certain embodiments, durvalumab or an antigen-binding fragment thereof is combined with tremelimumab administered at a dose of 75 mg (75 mg Q4W, IV) every 4 weeks, up to 4 doses per cycle, to treat bladder cancer, e.g. For example, subjects with UC are administered at a dose of 1500 mg (1.5 g) every 4 weeks (1500 mg Q4W, IV). In one embodiment, durvalumab is administered at a dose of 1,500 mg (1.5 g) (1500 mg Q4W, IV) every 4 weeks following this combination treatment. In one embodiment, the subject with bladder cancer, e.g., UC, has PD-L1 low/neg for PD-L1 expression; PD-L1 low; or is identified as having cancer or tumor cells or tissue that are PD-L1 high.

In some embodiments, at least two doses of durvalumab or an antigen-binding fragment thereof and tremelimumab or an antigen-binding fragment thereof are administered to the subject. In some embodiments, at least 3 doses, at least 4 doses, at least 5 doses, at least 6 doses, at least 7 doses, at least 8 doses, at least 9 doses, at least 10 doses, or at least 15 doses. A dose or more of one or both of the anti-PD-L1 antibody and/or anti-CTLA4 antibody may be administered to the subject. In some embodiments, durvalumab or an antigen-binding fragment thereof is administered over a 2-week treatment period, over a 4-week treatment period, over a 6-week treatment period, over an 8-week treatment period, over a 12-week treatment period, It is administered over a treatment period of 24 weeks, or over a treatment period of more than 1 year. In some embodiments, tremelimumab or an antigen-binding fragment thereof is administered over a 4-week treatment period, over an 8-week treatment period, over a 12-week treatment period, over a 16-week treatment period, over a 20-week treatment period, It may be administered over a 24-week treatment period, over a 36-week treatment period, over a 48-week treatment period, or over a treatment period of at least one year. In certain embodiments, durvalumab is administered Q2W or Q4W until the subject responds, until disease progression, or until unacceptable toxicity occurs. In yet other specific embodiments, durvalumab is co-administered with tremelimumab in Q2W or Q4W until the subject responds, until disease progression, or until unacceptable toxicity occurs.

The amount of durvalumab or antigen-binding fragment thereof and the amount of tremelimumab or antigen-binding fragment thereof to be administered to a subject with bladder cancer, particularly UC, will depend on the patient's age, weight, clinical evaluation, tumor burden, and/or the judgment of the attending physician. It will depend on various parameters such as other factors including:

In certain embodiments, subjects with bladder cancer, particularly UC, are administered durvalumab at a dose of 1 mg/kg to 20 mg/kg every two weeks (Q2W), especially at a dose of 1.5 g, for up to 4 doses per cycle. The antigen-binding fragment thereof is administered in combination with tremelimumab or its antigen-binding fragment at a dose of 1 mg/kg to 5 mg/kg of Q4W, especially at a dose of 75 mg. In certain embodiments, subjects with bladder cancer, particularly UC, are administered durvalumab at a dose of 1 mg/kg to 20 mg/kg every 4 weeks (Q4W), especially at a dose of 1.5 g, for up to 4 doses per cycle. The antigen-binding fragment thereof is administered in combination with tremelimumab or its antigen-binding fragment at a dose of 1 mg/kg to 5 mg/kg of Q4W, especially at a dose of 75 mg. In each of these embodiments, the patient is administered a 1.5 g dose of durvalumab or an antigen-binding fragment thereof of Q4W following administration of tremelimumab. In one embodiment, the antibody is administered to the subject by intravenous infusion.

Anti-PD-L1 antibodies or antigen-binding fragments thereof, such as durvalumab, and/or anti-CTLA4 antibodies or antigen-binding fragments thereof, such as tremelimumab, can be administered at any acceptable dosage known and used in the art. It can be administered by the route described. Without limitation, administration of one or more antibodies can be via intravenous (e.g., intravenous infusion), parenteral, or subcutaneous administration routes. In certain embodiments, administration is by intravenous (IV) infusion.

In certain embodiments, 10 mg/kg of durvalumab or antigen-binding fragment thereof is administered until the subject responds (e.g., achieves ORR, OS, PFS, or CR) to anti-PD-L1 antibody treatment. , is administered to subjects with bladder cancer, such as UC, every two weeks (Q2W), e.g., by intravenous infusion, until disease progression or until unacceptable toxicity occurs. In one embodiment, the intravenous infusion occurs over 60 minutes. In one embodiment, durvalumab is administered in combination with an anti-CTLA4 antibody, such as tremelimumab, simultaneously or at different predetermined times or administration cycles.

In certain embodiments, 1.5 g of durvalumab or an antigen-binding fragment thereof is administered to treat the disease until the subject responds (e.g., achieves ORR, OS, PFS, or CR) to anti-PD-L1 antibody treatment. It is administered to subjects with bladder cancer, such as UC, every 4 weeks (Q4W), e.g., by intravenous infusion, until progression or until unacceptable toxicity occurs. In one embodiment, durvalumab is administered in combination with an anti-CTLA4 antibody, such as tremelimumab, simultaneously or at different predetermined times or administration cycles.

In certain embodiments, 1.5 mg of durvalumab or an antigen-binding fragment thereof is administered in combination with administration of 75 mg of tremelimumab or an antigen-binding fragment thereof every 4 weeks (Q4W), for up to 4 doses per dosing cycle. , administered every 4 weeks (Q4W) to subjects with bladder cancer, such as UC. Administration of 1.5 g of durvalumab in Q4W is followed by 75 mg of tremelimumab in Q4W. In one embodiment, administration is by intravenous infusion. In certain embodiments, the combination of durvalumab or an antigen-binding fragment thereof and tremelimumab or an antigen-binding fragment thereof is administered until the subject responds to treatment (e.g., achieves ORR, OS, PFS, or CR). Administer until disease progression or until unacceptable toxicity occurs.

The methods provided herein have been found to reduce or delay bladder cancer tumor growth, particularly urothelial carcinoma tumor growth. In some embodiments, the reduction or delay in tumor growth can be statistically significant. Reduction in bladder cancer (e.g., UC) tumor growth can be measured by comparison of the growth of a subject's tumor at baseline time with expected tumor growth, either based on a large patient population or based on tumor growth in a control population. there is. Additionally, in a subject by an anti-PD-L1 antibody (e.g., durvalumab) or antigen-binding fragment thereof alone or in combination with an anti-CTLA4 antibody (e.g., tremelimumab) or antigen-binding fragment thereof. A reduction in bladder cancer (e.g., UC) tumor growth (or size) can be measured by comparing the growth or size of a subject's tumor at a given time after treatment to the growth or size of the tumor at a baseline time.

In certain embodiments, tumor response is measured using immune-related response criteria (irRc). In certain embodiments, tumor response is measured using Response Evaluation Criteria in Solid Tumors (RECIST). These response measurement techniques are known to and practiced by those skilled in the art.

In certain embodiments, a subject's response to bladder cancer treatment is detectable at about 1.5 to 7.5 months. In certain embodiments, the subject's response to bladder cancer treatment is about 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks. Detection is possible up to or between weeks 17, 18, 19, or 20 weeks. In certain embodiments, the subject's response to bladder cancer treatment is detectable at week 25, 28, 30, 33, 35, 40, 45, or 50, or between weeks. In certain embodiments, the subject's response to bladder cancer treatment is detectable at week 60, 65, 70, or later. In certain embodiments, the subject's response to bladder cancer treatment is durable such that the subject maintains the response for 6 months, 7 months, 8 months, 9 months, 10 months, 12 months, and longer periods of time during treatment according to the present methods. .

In certain embodiments, a subject treated according to a described method achieves disease control (DC), which also serves to refer to the subject's response. Disease control may be a complete response (CR), partial response (PR), or stable disease (SD). “Complete response” (CR) refers to the disappearance of all lesions, measurable or not, and the absence of new lesions. Confirmation can be obtained using consecutive repeat assessments over 4 weeks from the date of initial recording. New non-measurable lesions prevent CR. “Partial response” (PR) refers to a reduction in tumor burden of at least 30% compared to baseline. Confirmation can be obtained using consecutive repeat assessments at least 4 weeks from the date of initial recording. “Stable disease” (SD) indicates that a decrease in tumor burden of less than about 30% compared to baseline cannot be established and an increase of more than 20% compared to nadir cannot be established.

In certain embodiments, administration of durvalumab or an antigen-binding fragment thereof, alone as monotherapy, or in combination with tremelimumab or an antigen-binding fragment thereof, or in combination with standard treatment regimens, may be administered to the subject receiving treatment. May increase progression survival (PFS). In certain embodiments, administration of durvalumab or an antigen-binding fragment thereof alone as monotherapy, or in combination with tremelimumab or an antigen-binding fragment thereof, or in combination with a standard treatment regimen, may be administered to the entire population of the subject receiving treatment. May increase survival (OS).

In some embodiments, the subject has previously received treatment with at least one chemotherapeutic agent. In some embodiments, the subject has received treatment with at least two chemotherapy agents. The chemotherapeutic agent may be, for example and without limitation, vemurafenib, erlotinib, afatinib, cetuximab, carboplatin, bevacizumab, erlotinib, gefitinib, and/or pemetrexed. . In certain embodiments, the subject has received standard of care (SoC) treatment, including, for example and without limitation, a dual combination of cisplatin, carboplatin, cisplatin + gemcitabine, or carboplatin + gemcitabine. (See, e.g., R. Nagourney et al., 2008, Clin. Breast Cancer , Vol. 8, No. 5:432-435).

In some embodiments, the subject has 0, 1, or 2 Eastern Co. Active Oncology Group (ECOG) (Oken MM, et al. Am. J. Clin. Oncol. 5 :649-55 (1982)).

As provided herein, durvalumab or antigen-binding fragments thereof can also reduce free (soluble) PD-L1 levels. Free (soluble) PD-L1 refers to PD-L1 that is not bound (e.g., by durvalumab). In some embodiments, the sPD-L1 level is reduced/decreased after administration of durvalumab or an antigen-binding fragment thereof, or after administration of a combination of durvalumab or an antigen-binding fragment thereof and tremelimumab or an antigen-binding fragment thereof. or undetectable. In some embodiments, administration of durvalumab or an antigen-binding fragment thereof, or a combination of durvalumab or an antigen-binding fragment thereof and tremelimumab or an antigen-binding fragment thereof, may be administered, e.g., to free (soluble) PD prior to administration as described. -Reduces the rate of increase in free (soluble) PD-L1 levels compared to the rate of increase in L1 levels.

Bladder cancer or bladder tumors using durvalumab or an antigen-binding fragment thereof as provided herein, or a combination of durvalumab or an antigen-binding fragment thereof and tremelimumab or an antigen-binding fragment thereof (i.e., co-therapy), such as Treatment of subjects with UC may in some cases result in additive and/or synergistic effects. As used herein, the term “synergistic” refers to a combination of treatments (e.g., a combination of durvalumab or an antigen-binding fragment thereof with tremelimumab or an antigen-binding fragment thereof; or durvalumab or an antigen-binding fragment thereof refers to the combination of a fragment with another anti-cancer treatment or SoC treatment) being more effective than the additive effect of each of the single treatments.

The synergistic effect of a combination of treatments (e.g., a combination of durvalumab or an antigen-binding fragment thereof with tremelimumab or an antigen-binding fragment thereof) may result in lower doses of one or more therapeutic agents to subjects with bladder cancer or bladder tumors, such as UC. Allows the use of higher dosages and/or less frequent administration of the therapeutic agent. The ability to use lower doses of therapeutic agents and/or administer such therapeutic agents less frequently can reduce the toxicity associated with application of the therapy to a subject without reducing the efficacy of the therapy in the treatment of bladder cancer or bladder tumors, such as UC. decreases. Additionally, the synergistic effect may result in improved efficacy of the therapeutic agent in the management, treatment, or amelioration of solid bladder cancer tumors. The synergistic effect of the combination of therapeutic agents may avoid or reduce harmful or unwanted side effects associated with the use of each therapy alone (as a monotherapy), for example, at high doses.

In co-therapy, durvalumab or its antigen-binding fragment may optionally be comprised in the same pharmaceutical composition as tremelimumab or its antigen-binding fragment, or durvalumab or its antigen-binding fragment may be comprised in a separate pharmaceutical composition. . In this latter case, the pharmaceutical composition comprising durvalumab or an antigen-binding fragment thereof is suitable for administration before, simultaneously with, or after the administration of a pharmaceutical composition comprising tremelimumab or an antigen-binding fragment thereof. In certain cases, the administration of durvalumab or an antigen-binding fragment thereof to a subject as one composition overlaps the time of administration of tremelimumab or an antigen-binding fragment thereof as a separate composition.

The practice of the present invention utilizes routine techniques of molecular biology, microbiology, cell biology, biochemistry, immunohistochemistry and immunology (including recombinant techniques) that are within the understanding of those skilled in the art, unless otherwise indicated. Such techniques are described in "Molecular Cloning: A Laboratory Manual", second edition (Sambrook, 1989); “Oligonucleotide Synthesis” (Gait, 1984); “Animal Cell Culture” (Freshney, 1987); “Methods in Enzymology” “Handbook of Experimental Immunology” (Weir, 1996); “Gene Transfer Vectors for Mammalian Cells” (Miller and Calos, 1987); “Current Protocols in Molecular Biology” (Ausubel, 1987); “PCR: The Polymerase Chain Reaction”, (Mullis, 1994); It is fully explained in literature such as “Current Protocols in Immunology” (Coligan, 1991). These techniques are applicable to the production of polynucleotides and polypeptides of the invention and, accordingly, may be considered in making and practicing the invention. Techniques that are particularly useful for certain implementations will be discussed in the sections below.

The following examples are presented to provide those skilled in the art with a complete disclosure and explanation of how to construct and use the assay, screening, and treatment methods of the present invention, and are not intended to limit the scope of what the inventors regard as their invention.

Example 1 - Properties of durvalumab based on clinical analysis

This example provides an overview of the clinical pharmacology of durvalumab and demonstrates that this anti-PD-L1 antibody or antigen-binding fragment thereof may be used to treat urothelial carcinoma (UC) and urothelial carcinoma (UC) in subjects with bladder cancer, such as UC, and in need of treatment thereof. demonstrating that it exhibits properties and characteristics that support its suitability for use in the described method of treating bladder cancer.

A. Pharmacokinetics (PK) of durvalumab

The pharmacokinetics (PK) of durvalumab range from 0.1 to 10 mg/kg administered Q2W, or 15 mg/kg administered every 3 weeks (Q3W), or 20 mg/kg administered every 4 weeks (Q4W). The study studied 1,337 patients with solid tumors who received durvalumab. After durvalumab treatment at 10 mg/kg Q2W, PK was expected to be within the linear range and consistent with a typical monoclonal antibody (mAb). The main results of the PK analysis showed the following:

· Durvalumab exhibited non-linear PK at doses less than 3 mg/kg, which is believed to be due to saturable target-mediated clearance, and linear PK at doses above 3 mg/kg. The area under the concentration-time curve (AUC; days 0 to 14) increased dose-proportionally in the dose range of 0.1 to 3 mg/kg, and increased dose-proportionally at doses above 3 mg/kg. The maximum concentration (C _max ) increased in a dose-proportional manner within the dose range investigated.

· Steady state was achieved after approximately 16 weeks of repeated dosing. Systemic accumulation at C _max and trough concentration (C _trough ) was 0.64- to 1.87-fold and 3.39- to 4.93-fold, respectively, over the dose range investigated.

· Mean whole body linear clearance and central volume of distribution were 226 mL/day and 3.51 L, with moderate inter-subject variability of 29.3% and 21.2%, respectively. The estimated half-life was approximately 21 days after durvalumab was administered at a dose of 10 mg/kg Q2W.

· The durvalumab concentration (Km) accounting for the half maximum dose for non-linear clearance was approximately 0.5 μg/mL. Based on this estimate, target saturation of greater than 99% is expected at approximately 50 μg/mL of durvalumab. A dose of 10 mg/kg was expected to achieve this target exposure in >95% of patients.

· No dose adjustments were recommended at the suggested dose of durvalumab at 10 mg/kg Q2W IV based on patient baseline demographics or disease characteristics. Based on population PΛ analysis, age, weight, gender, positive anti-drug antibody (ADA), status, albumin level, LDH level, creatinine level, and soluble PD-L1 (sPD-L1) for the PK of durvalumab ) There was no clinically significant effect of level, tumor type, race, mild to moderate renal failure, mild liver injury, or ECOG status.

· Population PK modeling supported the use of a potential fixed dosing regimen of 750 mg Q2W IV or an equivalent but less frequent fixed dosing regimen of 1500 mg Q4W IV.

B. Immunogenicity of durvalumab

Overall, durvalumab demonstrated a low incidence of treatment-emergent ADA (2.6%; 37/1,412) with no clinically significant effect on PK after the 10 mg/kg Q2W IV dose.

In Study 1108 (ClinicalTrials.gov Identifier: NCT01693562), described in Example 2 below, 25 (2.5%) of 1,012 patients treated with durvalumab at doses ranging from 0.1 to 20 mg/kg developed treatment-induced ADA. and 3 (0.3%) patients had neutralizing antibodies. Among 970 patients treated with durvalumab at 10 mg/kg Q2W, including 191 patients in the UC cohort, 21 (2.2%) tested positive for treatment-induced ADA, and only 1 had neutralizing antibodies. It was detected in (0.1%) of patients. ADA titers ranged from 1 to 32 for most positive ADA samples (75% range, 1 to 4 [n = 43]; 21% range, 8 to 32 [n = 12]). The presence of ADA has not been shown to have a clinically significant effect on PK.

In contrast, in a study involving the treatment of patients with non-small cell lung cancer (NSCLC), 16 (3.6%) of 442 patients treated with durvalumab at 10 mg/kg Q2W developed treatment-emergent ADA. tested positive for and 2 (0.45%) patients had neutralizing antibodies. In that study, ADA titers were low and ranged from 1 to 16 for 95% (18/19) of the samples (one sample had a titer of 1,024). The presence of ADA did not appear to have a clinically significant effect on PK, safety, or efficacy in the study.

C. Pharmacodynamics and PK-PD relationship

Target binding: Dose-dependent inhibition of free soluble PD-L1 (sPD-L1) was observed following IV administration of durvalumab. After administration of durvalumab, complete sPD-L1 inhibition was observed near dose levels above 0.3 mg/kg. Following durvalumab administration at 10 mg/kg Q2W, >93% of patients demonstrated complete sPD-L1 suppression throughout the dosing interval.

Pharmacodynamic biomarkers: Mean proliferating CD8+ T cell mass at day 10 (mean ± standard of the mean [SEM]: 110% ± 27%) and day 15 (mean ± SEM: 67% ± 67%) following administration of 10 mg/kg durvalumab. 15%) significantly increased than the average of the volatility range. A similar trend was observed for proliferating CD4+ T cells at day 10 (mean ± SEM: 64% ± 18%), although the magnitude of the increase was not significantly above the range of variability (RV). Other lymphocyte populations also showed no mean change from baseline exceeding RV during the first 100 days of the study. These data indicate pharmacodynamic effects consistent with the proposed mechanism of action of durvalumab.

Impact of Exposure on Efficacy: Individually observed PK exposure (dose 1) for patients treated with durvalumab at 10 mg/kg Q2W IV in the UC cohort of the study described herein (Study 1108, Example 2) concentration at the end of infusion [C _max,1 ], pre-infusion of dose 1 or 2 [C _min,2 ], pre-infusion at steady state [C _min,ss ]) and clinical efficacy endpoints (ORR assessed by BICR). and DoR) were not confirmed. These results are consistent with exposure-response analysis.

Impact of exposure on safety: individually observed PK exposure (C _max,1 , C _min,2 , and C _min,ss ) and adverse events ((AEs), treatment-related AEs, AESIs, treatment-related AESIs ( Association between treatment with durvalumab at 10 mg/kg Q2W IV in Study 1108 (further categorized by any grade, grade 2 or higher, grade 3 or higher), AEs resulting in permanent discontinuation of durvalumab) It was not confirmed in any patient. Slight reversal (fewer AEs with higher exposure) and increasing (more AEs with higher exposure) trends were observed. These trends appeared to be random changes and were not considered clinically relevant because trends were often contradictory and inconsistent across trials, types of AEs, or PK metrics.

Dosage Rationale: The proposed dosing regimen of durvalumab at 10 mg/kg Q2W was supported by robust datasets from clinical and nonclinical trials. Some of the key features included the following: (i) Durvalumab treatment was well tolerated. No dose-limiting toxicities were observed at durvalumab doses of 10 mg/kg Q2W or 20 mg/kg Q4W; (ii) clinically meaningful efficacy as discussed in Example 2 with respect to the UC cohort of the clinical study (Study 1108); (iii) Achievement of target exposure based on clinical PK/PD: durvalumab PK approached linearity at Q2W doses above 3 mg/kg (trough concentration of approximately 50 μg/mL), indicating complete target saturation. Indicates target saturation. Population PK simulations indicated that after a dose regimen of durvalumab of 10 mg/kg Q2W, >95% of patients would achieve a target trough concentration of 50 μg/mL or greater to achieve complete target saturation. (iv) Achievement of target exposure based on non-clinical efficacy model: durvalumab at 10 mg/kg Q2W exceeds 100 μg/mL (identified as the target concentration of durvalumab resulting in maximal tumor growth inhibition in the mouse model) Achieved the median lowest concentration of (v) There is no clear association of PK exposure with efficacy or safety: no exposure-efficacy relationship was identified in the UC cohort of Study 1108, after administration of 10 mg/kg durvalumab in Study 1108 (or anti-PD in NSCLC). -No clear exposure-safety relationship was identified in the safety population of studies involving L1 antibody treatment; (vi) An incidence of ADA of 2.6% (37 of 1,412 patients) was observed following administration of 10 mg/kg Q2W of durvalumab, without clinically significant effects on PK. Therefore, observed clinical activity in UC patients coupled with a manageable safety profile and supportive interpretative correlations support administration of durvalumab at a dose of 10 mg/kg Q2W IV for the treatment of subjects with UC. did.

D. Duration of treatment

The optimal duration of anti-PD-1/PD-L1 therapy is still unclear, but in clinical trials the duration of anti-PD-1/PD-L1 therapy has been shown to be up to 12 months, 24 months, or until disease progression. Varies. Without wishing to be bound by theory, anti-PD-1/PD-L1 antibodies do not alter the expression of PD-L1 on tumor cells (TC) or tumor-associated immune cells (IC) and do not alter the expression of PD-L1 and PD-L1. Because it primarily biologically blocks the interaction of -1, sequential blockade can optimally prevent T cell exhaustion. Previous protocols involving durvalumab used limited treatment durations with the option for retreatment. Because an acceptable safety profile has been demonstrated for long-term dosing and the occurrence of new AEs has been shown to reach a plateau before 12 months of treatment, all durvalumab protocols include continuous treatment until disease progression. On balance, the potential benefit of allowing patients who benefit from durvalumab to continue treatment beyond 12 months is justified based on ongoing risks. For this reason, the study described in Example 2 includes treatment of bladder cancer (e.g., UC) in subjects until disease progression.

Example 2 - Clinical trial involving treatment of subjects with bladder cancer (UC) with durvalumab

A. Overall trial design

Data related to the methods described herein are provided by ongoing study 1108, a phase 1/2, single-arm, open-label, multicenter clinical trial (ClinicalTrials.gov Identifier: NCT01693562). The dose-escalation phase of the study included 17 tumor-specific cohorts, including the urothelial bladder cancer (UC) cohort. Patients were treated in the dose-escalation phase and continued with durvalumab at 10 mg/kg Q2W.

We initiated a UC expansion cohort unrestricted for prior course of therapy, in which approximately 60 patients with histologically or cytologically confirmed UC were to be enrolled, with the first 20 patients enrolled regardless of PD-L1 expression. , follow-up 40 patients were required to have more than 5% tumor cells positive for PD-L1 expression. Thereafter, histologically or cytologically confirmed inoperable or metastatic transitional cells (including transitional cells and mixed transitional cell/non-transitional cell histology) of the urothelium (including the bladder, ureters, urethra, and renal pelvis). 132 additional patients with carcinoma were enrolled, regardless of PD-L1 expression, who received one to two lines of neoadjuvant systemic therapy, including platinum-based therapy. In particular, these patients must have received at least one but no more than two prior lines of systemic therapy, including standard platinum-based therapy for inoperable or metastatic disease, and their disease must have progressed or been refractory to such systemic therapy. It was. Prior confirmed chemoradiation, adjuvant treatment, or neoadjuvant treatment for locally advanced disease was considered to be the first-line treatment, provided that disease progression occurred less than 12 months after treatment (for chemoradiation and adjuvant treatment) or (for neoadjuvant treatment) occurred less than 12 months after surgery. The progression of the interval between two lines of treatment defines separate lines of treatment.

The primary endpoint for the UC cohort was confirmed objective response (OR) according to RECIST v1.1 as determined by independent blinded central review (BICR). Key secondary endpoints included DoR, disease control rate (DCR), PFS, and OS.

B. Patient population

Eligible patients were 18 years of age or older with histologically or cytologically confirmed locally advanced or metastatic UC. Eligibility criteria based on prior course of treatment are as set forth in (A) above. Patients had an ECOG performance score of 0 or 1, adequate organ and blood function, and fresh tumor biopsy and/or archival tumor tissue available for PD-L1 testing. Tests include history of immunodeficiency; Medical conditions requiring systemic immunosuppression; History of severe immune-mediated adverse reactions; Untreated central nervous system metastases; and patients with human immunodeficiency virus, active tuberculosis, or hepatitis B or C infection were excluded.

C. Efficacy Endpoints and Analysis

Interim efficacy analysis

103 UC patients treated with durvalumab 10 mg/kg Q2W and with the opportunity to be followed for at least 13 weeks (i.e., at least 2 follow-ups assessed according to RECIST v 1.1 at weeks 6 and 12 and in a 1-week visit window) An interim analysis of efficacy was performed after the patient had the opportunity to undergo scrutiny.

The analysis population used for the interim efficacy analysis was primary, defined as treated UC patients who had the opportunity to be followed for at least 13 weeks until the DCO date (i.e., received the first dose of durvalumab at least 13 weeks before the DCO date). This was the Primary Efficacy Population. This was the primary analysis population for the interim+ analysis of all efficacy data, and the Supportive Efficacy Population was the population with the opportunity to be followed for at least 24 weeks until the DCO date (i.e., those who received durvalumab at least 24 weeks before the DCO date). defined as all treated UC patients (who received the first dose). This was the support analysis group for the interim efficacy analysis.

Primary efficacy analysis

The primary efficacy endpoint was objective response (OR), defined as the best overall response of confirmed CR or partial response (PR) according to RECIST v1.1 as determined by BICR. ORR, defined as the proportion of patients with OR, was calculated, and the 95% accurate two-sided CI of ORR was estimated using the Clopper-Pearson method. Patients were screened for disease assessment at baseline, at weeks 6, 12, and 16 after initiation of durvalumab therapy, and then every 8 weeks during treatment. After discontinuation of treatment, patients were examined every 2 months for 1 year and then every 3 months until objective disease progression was confirmed.

The primary interim analysis of ORR (exact 95% CI) was performed on all treated UC patients (primary efficacy population described above) who had the opportunity to be followed for at least 13 weeks. Support analysis of ORR was performed on all treated UC patients who had the opportunity to be followed for at least 24 weeks (support efficacy population as described above). Additionally, a subgroup of all treated UC patients whose disease progressed during or after platinum-based therapy, including patients whose disease progressed within 12 months of treatment (2L+ post-platinum) in the neoadjuvant/adjuvant setting. A similar analysis of ORR was performed for .

Secondary efficacy analysis

Secondary efficacy endpoints included DoR, DCR, time to response, PFS, BICR, and change in target lesion size according to RECIST v1.1 as determined by investigator assessment, and OS. Membranous PD in tumor cells (TCs) by trained pathologists in the evaluation of the validated VENTANA PD-L1 (SP263) assay to evaluate PD-L1 expression associated with the antitumor activity of durvalumab in UC patients. Efficacy data were also analyzed by subgroups identified based on PD-L1 expression as determined by -L1 staining and overall PD-L1 staining of tumor-associated immune cells (IC). A total of 103 UC patients gave the width between the observed ORR and its lower limit of the exact two-sided 95% CI, ranging from 7% to 9%, when the ORR was expected to be in the 20% to 30% range.

D. Evaluation of PD-L1 expression using a validated PD-L1 detection assay

We developed a scoring algorithm to distinguish responsive and non-responsive patients based on PD-L1 expression cutoffs. The relationship between PD-L1 expression levels on both tumor cells (TC) and immune cells (IC) and response to durvalumab therapy was assessed in tumor samples from treated patients in the UC cohort of Study 1108. This analysis established that the optimal algorithm was the combined evaluation of PD-L1 staining of TC and IC.

To determine the primary PD-L1 subgroup for analysis, a cutoff was established for responders to durvalumab monotherapy. This cutoff was determined using a training data set consisting of an initial group of enrolled subjects who were followed for at least 12 weeks. PD-L1 expression data based on RECIST v1.1 and ORR data evaluated by researchers from these subjects were used to define a PD-L1 expression threshold that best discriminates between responsive and non-responsive subjects. Other RECIST v1.1 data by the investigators (such as rate of change from baseline in target lesions) and clinical data (such as discontinuation due to PD or early death) were considered. The optimal algorithm is to have PD-L1 high tumors when baseline PD-L1 expression is ≥25% on TC or IC, or PD-L1 low/negative tumors when baseline PD-L1 expression is <25% on TC and IC. Patients were classified as having . Based on this cutoff, the first version of the algorithm was defined (Development Algorithm).

The rationale for the 25% cutoff for TC was based on:

1. Biology and response of PD-L1: High membranous tumor cell PD-L1 expression has been found to correlate with better clinical response associated with drugs targeting the PD-1/PD-L1 pathway.

2. Prevalence of UC: In evaluation of PD-L1 expression in commercial bladder cancer samples, PD-L1 was found to be highly expressed in some cases of TC, suggesting congenital or adaptive overexpression of PD-L1; and

3. Clinical outcome data in UC: one of the subjects with a partial response (PR) and another with the best change of -38.5 had PD-L1 >25% in TC.

Similarly, the rationale for the 25% cutoff for IC was based on:

1. Biology of PD-L1 and response in UC: High PD-L1 expression in IC was found to correlate with better clinical response associated with the anti-PD-L1 drug atezolizumab.

2. Prevalence of UC: Among commercial bladder cancer samples, PD-L1 was found to be highly expressed in IC in many cases, suggesting adaptive overexpression of PD-L1; and

3. Clinical outcome data in UC: All 4 subjects with PR had PD-L1 >25% in IC.

Another important factor considered for selection of the 25% cutoff for both TC and IC is interreader precision (pathologist The reproducibility between groups was at the expected level. Among subjects with high PD-L1 (>25% in TC or IC), the investigator-assessed ORR according to RECIST v1.1 in training subjects was 36.4% (4/11, 95% CI: 10.9, 69.2); The ORR in PD-L1 low/negative subjects (<25% in TC and IC) was 0%. The combined algorithm yields a higher negative predictive value (NPV) and a higher true positive rate (TPR) than scoring TC or IC alone.

The assay protocol for PD-L1 staining was locked before patient testing, and the algorithm was locked after reading the 20 patient training set. The Final Algorithm (Table 1), implemented later in the trial and at the start of adding patients (132 patients) to the study, was developed, which states that if PD-L1 expression on the IC is 1% or less, It consisted of modifications to the Development Algorithm to improve scoring accuracy:

These modifications to the algorithm improved the accuracy of scoring in cases with low levels of IC invasion while maintaining 100% agreement between the development and final algorithms.

Application of the scoring algorithm to determine PD-L1 status (high vs. low/negative) was performed programmatically based on raw data collected while the pathologist assessed the percentage of PD-L1 TC and IC staining cells. The final algorithm was applied prospectively to samples from 43 patients in the primary efficacy group and retrospectively to 63 patients in the primary efficacy group. Without intending to be limiting, the PD-L1 detection assay (VENTANA PD-L1 (SP263) assay) may serve as a complementary diagnostic assay, as it can be used to assess PD-L1 expression and to evaluate dermal function across the UC population. This is because it can provide useful information about the possibility of reaction to Mab.

PD-L1 expression cutoffs and initial scoring algorithms were defined based on a training set of 20 UC subjects (the first 20 UC subjects enrolled in Study 1108), with PD-L1 elevation originally defined as TC ≥25% or IC ≥25%. PD-L1 low/negative was defined as baseline PD-L1 expression with TC less than 25% and IC less than 25% (Development Algorithm). Later in the study, the Final Algorithm was developed, which consisted of a modification of the Development Algorithm, and if the IC area represented 1% or less of the total tumor area, PD-L1 expression status was defined as follows: Baseline PD PD-L1 high was when -L1 expression was TC of 25% or greater or IC = 100%, and PD-L1 low/negative was when baseline PD L1 expression was TC of less than 25% and IC of less than 100%. Addition of this rule improved the accuracy of scoring when IC content was low.

E. Patient population studied

Of the 103 UC patients in the primary efficacy population, 94 were 2L+ platinum-treated with disease progression during or after platinum-based therapy, including patients with disease progression within 12 months of receiving therapy in the neo-adjuvant/adjuvant setting. He was a patient after that. The remaining nine patients were either treatment naïve or were designated as 1L patients who received platinum-based therapy in the neo-adjuvant/adjuvant setting and had disease progression 12 months after the last dose of therapy. Seven of the nine treatment-naive/1L patients were considered cisplatin ineligible based on the cisplatin eligibility criteria used in this study.

The population of UC patients treated in Study 1108 represented a well-defined population with high unmet clinical need and provided the intended population to be treated in clinical practice. Inclusion criteria were designed to accurately define the study population relevant to current clinical practice in the intended target population and to exclude patients whose participation would have been inappropriate for safety reasons. The median age of patients was mid-60s, most patients were male, and most had an ECOG status of 1 at study entry (Table 2). The majority of patients had received one or two prior lines of treatment at study entry. All but three patients had received prior platinum-based therapy, either cisplatin-based (69.9%) or carboplatin-based (27.2%). Baseline disease characteristics indicated a study population with poor prognosis (Table 2). Approximately 95% of the primary efficacy population, including nearly 50% with liver metastases, had visceral disease, with 36.9% having received at least two prior lines of systemic therapy and 14.6% having received three or more prior lines of therapy. I have had treatment.

F. Efficacy

Objective response rate (ORR), duration of response (DoR), and disease control rate by BICR

Durvalumab monotherapy demonstrated significant benefit in patients with locally advanced or metastatic UC based on endpoints predictive of clinical benefit (ORR, DoR). In the primary efficacy population, durvalumab monotherapy resulted in an ORR of 20.4% (95% CI: 13.1%, 29.5%) by BICR according to RECIST v1.1 in all UC patients and in the 2L+ post-platinum subgroup. This resulted in an ORR of 20.2% (95% CI: 12.6%, 29.8%) (Table 3). Three additional patients had unconfirmed responses according to BICR at the time of DCO with possible confirmation as follows: of the three patients still on treatment, one had a confirmed PR according to BICR based on follow-up work-up after DCO; Of the three patients still on treatment, the second patient was evaluated as PR on two consecutive work-ups, but the interval between the two work-ups was 26 days (less than 4 weeks); Of the three patients still on treatment, the third had an initial PR at the second work-up (week 12) and was likely confirmed.

Patient responses occurred early during treatment and were durable. Median time to response among 21 responders was 1.41 months (range, 1.2 to 7.2). The median DoR was not reached (range, 1.4+ months to 19.9 months). A total of 16 patients maintained a response for at least 6 months, and 7 patients maintained a response for at least 9 months. Of the 21 responders, 18 (85.7%) had an ongoing response at the time of DCO. Of the 3 patients who progressed after initial response as assessed by BICR, all 3 completed 12 months of treatment with durvalumab dosed at 10 mg/kg Q2W and had no significant improvement in target lesions at day 286 (disease assessment 6). We included one patient who progressed due to augmentation. This patient had a follow-up CR per BICR starting at day 392 (disease assessment 8) and remained in ongoing CR through the last follow-up at the time of DCO at day 650 (disease assessment 12). The UC subgroups after 2L+ platinum treatment showed similar efficacy (Table 3).

G. PD-L1 subgroup analysis

Durvalumab demonstrated clinical activity and durability of response in both PD-L1 high and PD-L1 low/negative subgroups, but the combined algorithm using TC/IC in the VENTANA PD-L1 (SP263) assay showed a high TPR. (85.7%) and high NPV (92.3%). In contrast, the TC-only or IC-only algorithms are not discriminatory, as indicated by lower TPR and NPV. These data support the utility of an algorithm based on TC or IC combined to identify subjects more likely to respond to durvalumab. Additionally, given the high NPV of the assay, it is particularly helpful in informing patients of the likelihood of response to durvalumab, i.e., subjects classified as PD-L1 high by the VENTANA PD-L1 (SP263) assay. tended to have a higher ORR than PD-L1 low/negative subjects. The combined algorithm supports the utility of the assay to identify subjects most likely to respond to durvalumab but not completely exclude subjects who may respond. The sponsor considered that the high NPV of the assay is particularly helpful in informing patients of the likelihood of response to durvalumab but should not be used to exclude subjects from treatment, as this may be due to PD-L1 low/negative symptoms. Three valumab-treated subjects had clinical responses (1 PR and 2 complete responses), as responses were still ongoing at DCO.

Clinical activity was observed across PD-L1 high and PD-L1 low/negative subgroups. ORR was 29.5% (18/61; 95% CI: 18.5%, 42.6%) in the PD-L1 high subgroup and 7.7% (3/39; 95% CI: 1.6%) in the PD-L1 low/negative subgroup. , 20.9%). CR was observed in both subgroups: PD-L1 high, 3 (4.9%) patients, and PD-L1 low/negative, 2 (5.1%) patients. The responses observed in both subgroups were durable.

H. Support efficacy analysis

In the supportive efficacy population, ORR was 28.6% (95% CI: 17.9%, 41.3%) for all UC patients and 29.6% (95% CI: 18.0%, 43.6%) for patients after 2L+ platinum (Table 4). The median duration of response was not reached. Similar to the primary efficacy population, clinical activity was observed across PD-L1 high and PD-L1 low/negative subgroups. ORR was 40.0% (16/40; 95% CI: 24.9%, 56.7%) in the PD-L1 high subgroup and 8.7% (2/23; 95% CI: 1.1%) in the PD-L1 low/negative subgroup. , 28.0%). CR was observed across both subgroups: PD-L1 high, 2 (5.0%) patients, and PD-L1 low/negative, 2 (8.7%) patients. The responses observed in both subgroups were durable.

I. Progression-free survival by BICR

Median progression-free survival (PFS) in the primary efficacy group was 2.2 months (95% CI: 1.4, 2.7). The PFS rate at 6 months was 28.3% (95% CI: 19.3%, 37.9%). Median PFS was 2.5 months in the PD-L1 high subgroup and 1.5 months in the PD-L1 low/negative subgroup. The PFS rate at 6 months was 39.2% (95% CI: 26.4%, 51.8%) for the PD-L1 high subgroup and 13.4% (95% CI: 4.2%, 28.1%) for the PD-L1 low/negative subgroup. %).

J. Overall survival

Median overall survival (OS) in the primary efficacy population was 14.1 months (95% CI: 4.5, not estimable). OS rates at 6, 9, and 12 months were 60.3% (95% CI: 48.7%, 70.1%), 55.7% (95% CI: 43.2%, 66.4%), and 52.4% (95% CI), respectively. : 39.1%, 64.1%) (Table 5). The median OS was not reached in the PD-L1 high group and was 3.3 months in the PD-L1 low/negative group. Figure 4 shows Kaplan-Meier estimates of OS.

K. Efficacy by subgroup

Objective responses (ORs) were observed based on baseline demographics or disease characteristics across all subgroups, including those with poor prognosis, such as patients with visceral or liver metastases. In the primary efficacy cohort, the ORR in the subgroups for visceral metastases, liver metastases, and lymph node alone was 19.4% (19/98; 95% CI: 12.1%, 28.6%) and 10% (5/50; 95% CI: 3.3%, 21.8%) and 40% (2/5; 95% CI: 5.3%, 85.3%). Although numerical differences in point estimates were noted across some subgroups, sample sizes were small and 95% CIs overlapped for most subgroup comparisons, with the exception of tumor burden where patients with tumor burden below the median showed higher ORR. It has been done. Similar ORRs were observed for major subgroups, including region, prior line of therapy, baseline creatinine clearance, primary tumor site, and prior platinum therapy.

Data from another clinical study in which durvalumab was used for the treatment of patients with NSCLC are consistent with other anti-PD-1/PD-L1 therapies in patients with locally advanced or metastatic NSCLC who have received at least 2 lines of prior systemic therapy. response and sustained activity were also supported. Studies in NSCLC patients add supportive value to the clinical activity of durvalumab. For example, Cohort 2 of the NSCLC Study included 265 patients with epidermal growth factor receptor/anaplastic lymphoma kinase wild-type NSCLC treated with durvalumab 10 mg/kg Q2W, with mature data following >12 months of follow-up. had ORR was observed as a sustained response across PD-L1 high and PD-L1 low/negative subgroups, i.e. ORR was 16.4% (95% CI: 10.8, 23.5) for PD-L1 high subgroup and PD-L1 low/negative subgroup. for the low L1/vocal subgroup it was 7.5% (95% CI: 3.1, 14.9). At the time of DCO, the median DoR was 12.3 months for patients in the PD-L1 high subgroup and was not reached in the PD-L1 low/negative subgroup. In the NSCLC study, the median OS in the PD-L1 high subgroup and PD-L1 low/negative subgroup was 10.9 months and 9.3 months, respectively.

L. Conclusion of the clinical study

objective response

Durvalumab monotherapy showed significant benefit in patients with locally advanced or metastatic UC based on objective response rate (ORR) and duration of response (DoR), which are endpoints that predict clinical benefit compared to commonly used treatments. indicated. More specifically, in the primary efficacy population (all UC patients with an opportunity for follow-up of at least 13 weeks), the ORR was BICR according to RECIST v1.1, including 5 patients (4.9%) with a best response of CR. by 20.4% (21/103; 95% CI: 13.1%, 29.5%). The ORR in patients with UC after 2L+ platinum treatment was 20.2% (19/94; 95% CI: 12.6%, 29.8%). Additionally, 3 patients (all still on treatment at DCO) had undetermined responses at DCO. In the supportive efficacy population (UC patients with at least 24 weeks of follow-up), the ORR was 28.6% (18/63; 95% CI: 17.9%, 41.3%). The ORR in patients with UC after 2L+ platinum treatment was 29.6% (16/54; 95% CI: 18.0%, 43.6%).

duration of reaction

In Study 1108 for the treatment of bladder cancer, responses occurred early in treatment and were durable. Median time to response was 1.41 months (range, 1.2 to 7.2 months). The median DoR has not yet been reached (range, 1.4+ months to 19.9+ months). At the time of DCO, 18 of 21 responders (85.7%) had an ongoing response; Sixteen patients had a DoR greater than 6 months; Nine patients had a DoR greater than 9 months. Among the three patients whose disease progressed by BICR according to RECIST v1.1, all completed 12 months of treatment with durvalumab. One of these patients had disease progression due to increased target lesions but had a subsequent CR according to BICR, which was maintained until the last follow-up at the time of DCO at day 650.

Progression-free survival (PFS)

Median PFS in the primary efficacy population was 2.2 months (95% CI: 1.4, 2.7). The PFS rate at 6 months was 28.3% (95% CI: 19.3%, 37.9%).

Overall Survival (OS)

OS results were encouraging in the heavily pretreated UC population. Median OS was 14.1 months (95% CI: 4.5, not estimable); OS rates at 6, 9, and 12 months were 60.3% (95% CI: 48.7%, 70.1%), 55.7% (95% CI: 43.2%, 66.4%), and 52.4% (95% CI), respectively. : 39.1%, 64.1%).

Clinical activity in subgroups

Clinical activity in the primary efficacy population was PD-L1 high and PD-L1 low (as defined by TC or IC 25% PD-L1 expression using the validated VENTANA PD-L1 [SP263] assay). This was observed across the negative subgroup and across various baseline disease subgroups, including the poor prognosis subgroup. In the PD-L1 high subgroup, ORR was 29% (18/61; 95% CI: 18.5%, 42.6%). In the PD-L1 low/negative subgroup, ORR was 7.7% (3/39; 95% CI: 1.6%, 20.9%). CR was observed in both subgroups: PD-L1 high, 3 patients (4.9%) and PD-L1 low/negative, 2 patients (5.1%). ORR was 19.4% (19/98; 95% CI: 12.1%, 28.6%) and 10% (5/50; 95% CI: 3.3%, 21.8%) in the visceral metastases, liver metastases, and lymph node-only subgroups, respectively. and 40% (2/5; 95% CI: 5.3%, 85.3%).

Compelling efficacy and safety data from the UC cohort of Study 1108 (UC Target Population) are available for the treatment of patients with locally advanced or metastatic bladder cancer, e.g., UC, whose disease progressed during or after first-line standard platinum-based therapy. Supports the data disclosed herein for the use of durvalumab in. In the UC cohort, the treatment regimen of durvalumab dosed at 10 mg/kg Q2W resulted in an ORR of 20.4% (21/103; 95% CI: 13.1%, 29.5%), a significant improvement over commonly used regimens. brought it Responses occurred early during treatment and were durable. Among the 21 responders, the median time to response was 1.41 months (range 1.2 to 7.2). The median DoR was not reached (range, 1.4+ months to 19.9+ months); Sixteen patients maintained a response for at least 6 months, and 7 patients maintained a response for at least 9 months. Eighteen of 21 responders (85.7%) had an ongoing response at the time of DCO. Three responders followed up according to RECIST v1.1 criteria completed the entire 12-month course of durvalumab therapy and were alive.

Responses were observed in the PD-L1 high subgroup (29.5%; 18/61 [95% CI: 18.5%, 42.6%]) and PD-L1 low/negative subgroup (7.7%; 3/39 [95% CI: 1.6%]). , 20.9%]) were observed in both, and persistence data were comparable to the overall UC cohort. The median OS in the UC cohort was 14.1 months, and the OS rates at 6 and 9 months were 60.3% and 55.5%, respectively. These rates generally exceeded the survival benefit from chemotherapy after platinum treatment. Among the UC cohort, common AEs (>10%) were consistent with the underlying disease and included fatigue, constipation, decreased appetite, nausea, anemia, back pain, fever, urinary tract infection, diarrhea, peripheral edema, dyspnea, and vomiting. . The incidence of treatment-related grade 3 or 4 AEs (5.2%) and treatment-related AEs resulting in death (1.0%) or permanent discontinuation of durvalumab (3.7%) was low and consistent across patient populations, which The well-tolerated safety profile of this therapy for the treatment of bladder cancer, such as UC, is supported. Two treatment-related deaths occurred, both due to autoimmune hepatitis and pneumonia (imAE).

Significant risks associated with the use of durvalumab (i.e., immune-mediated pneumonitis, hepatitis, diarrhea or colitis, endocrinopathy (e.g., hyperthyroidism, hypothyroidism, adrenal insufficiency and hypopituitarism, type 1 diabetes) ), nephritis, dermatitis or rash, and infusion-related reactions) occurred at low rates, were generally of low severity, and were manageable through established treatment guidelines. In the UC cohort, 89 (46.6%) patients had an adverse event of special interest (AESI) and 15 (7.9%) patients had an event identified as an imAE. One patient permanently discontinued durvalumab due to imAEs. The most common imAEs (>1% of patients) fell into the categories of hypothyroidism (3.7%) and selected hepatic events (1.6%). Three patients had grade 3 or 4 imAEs, including increased ALT, increased AST, increased transaminases, maculopapular rash, and acute kidney injury (tubulointerstitial nephritis).

According to the methods and results described in the treatment of bladder cancer, such as UC, the anti-PD-L1 antibody durvalumab is clinically effective (including complete responses) in both PD-L1 high and PD-L1 low/negative subgroups. Durability of activity and response was observed, with no appreciable difference in safety profile. Therefore, knowledge of PD-L1 expression is not essential for safe and effective use of durvalumab. However, the PD-L1 status of a patient's tumor can help determine the benefits and risks of a patient's treatment options and can help set treatment expectations during physician-patient conversations.

Currently, no effective or standard second-line (2L) treatment exists for patients with locally advanced or metastatic UC whose disease has progressed after platinum-based therapy. The mainstay of current treatment is significant toxicity, such as neutropenia (7% to 83%), anemia (11% to 27%), thrombocytopenia (6% to 23%), pain (39%), and infection (6%). with chemotherapy that has a low ORR (approximately 10%) and an OS range of approximately 6 to 9 months. The rates of clinically significant AEs in patients treated with durvalumab compared favorably with commonly used therapies, and the nature and frequency of imAEs were generally consistent with rates in patients treated with atezolizumab. .

Treatment of subjects with bladder cancer, such as UC, with durvalumab at a dose of 10 mg/kg Q2W was found to have a favorable benefit:risk profile for this indication. Both robust ORR and durability of response are two surrogate endpoints determined from studies that support clinical benefit and a favorable tolerability profile in areas where no treatment is available. Given the high unmet medical need for patients with locally advanced or metastatic UC, whose disease has progressed during or after standard platinum-based therapy, it is a serious, life-threatening disease lacking robust and beneficial treatment options. There is a need in the art to use durvalumab to treat bladder cancer and UC. Accordingly, the present method comprising durvalumab administered to a subject with bladder cancer at a dose of 10 to 20 mg/kg Q2W or Q4W, especially at a dose of 10 mg/kg Q2W, is a clinically available method for bladder cancer patients in need of treatment. Provides treatment regimens that provide beneficial results.

Example 3

Combination of durvalumab and tremelimumab to treat bladder cancer, e.g., UC

A confirmatory clinical trial (DANUBE) supports the clinical study described in Example 2 for the use of durvalumab in the treatment of UC. The supportive clinical study is durvalumab monotherapy (1.5 g every 4 weeks (Q4W)) against 1L chemotherapy, which is the standard (SoC) (cisplatin + gemcitabine or carboplatin + gemcitabine doublet, based on cisplatin eligibility). IV); Or a trial to determine the efficacy and safety of durvalumab (1.5 g IV Q4W) followed by durvalumab (1.5 g IV Q4W) in combination with tremelimumab (75 mg IV Q4W) for up to 4 doses per cycle. This is a phase 3 randomized, open-label, controlled, multicenter, global trial. In this study, patients had treatment-naive, histologically or cytologically documented unresectable stage IV transitional cell carcinoma (transitional cell and mixed transitional cell) of the urothelium (including the renal pelvis, ureters, bladder, and urethra). /non-transitional cell histology). Patients will be randomized (1:1:1) to treatment with durvalumab + tremalimumab combination therapy, durvalumab monotherapy, or SoC therapy. The primary objective was to evaluate the efficacy of durvalumab + tremelimumab combination therapy versus SoC treatment in terms of PFS and OS in all UC patients with UC cancer identified as PD-L1 high (PD-L1-high UC patients). Alternatively, to evaluate the efficacy of durvalumab monotherapy versus SoC treatment in terms of OS in patients with UC with tumor cells or tissue. An important secondary objective is to evaluate the efficacy of durvalumab monotherapy versus SoC treatment in terms of PFS in PD-L1 high UC patients and in terms of PFS and OS in all UC patients. The study has 625 randomized patients to date, and enrollment is ongoing. PFS showing intermediate OS will be analyzed as the study progresses, with final OS assessment at the end of the study.

Other Implementations

From the foregoing description, it will be apparent that variations and modifications may be made to the invention described herein to adapt it to various uses and conditions. Such embodiments are also within the scope of the following claims.

Reference to a list of elements in any definition of a variable herein includes definition of that variable as any single element or combination (or sub-combination) of the listed elements. Reference to an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

All patents and publications mentioned herein are herein incorporated by reference to the same extent as if each independent patent or publication was specifically and individually indicated to be incorporated by reference.

SEQUENCE LISTING <110> MEDIMMUNE, LLC <120> ANTI-PD-L1 ANTIBODY TREATMENT OF BLADDER CANCER <130> B7H1-220-WO-PCT <140> PCT/US2018/018513 <141> 2018-02-16 <150> 62/459,700 <151> 2017-02-16 <160> 18 <170> PatentIn version 3.5 <210> 1 <211> 176 <212> PRT <213> Homo sapiens <400> 1 Met Arg Ile Phe Ala Val Phe Ile Phe Met Thr Tyr Trp His Leu Leu 1 5 10 15 Asn Ala Pro Tyr Asn Lys Ile Asn Gln Arg Ile Leu Val Val Asp Pro 20 25 30 Val Thr Ser Glu His Glu Leu Thr Cys Gln Ala Glu Gly Tyr Pro Lys 35 40 45 Ala Glu Val Ile Trp Thr Ser Ser Asp His Gln Val Leu Ser Gly Lys 50 55 60 Thr Thr Thr Thr Asn Ser Lys Arg Glu Glu Lys Leu Phe Asn Val Thr 65 70 75 80 Ser Thr Leu Arg Ile Asn Thr Thr Thr Asn Glu Ile Phe Tyr Cys Thr 85 90 95 Phe Arg Arg Leu Asp Pro Glu Glu Asn His Thr Ala Glu Leu Val Ile 100 105 110 Pro Glu Leu Pro Leu Ala His Pro Pro Asn Glu Arg Thr His Leu Val 115 120 125 Ile Leu Gly Ala Ile Leu Leu Cys Leu Gly Val Ala Leu Thr Phe Ile 130 135 140 Phe Arg Leu Arg Lys Gly Arg Met Met Asp Val Lys Lys Cys Gly Ile 145 150 155 160 Gln Asp Thr Asn Ser Lys Lys Gln Ser Asp Thr His Leu Glu Glu Thr 165 170 175 <210> 2 <211> 3349 <212> DNA <213> Homo sapiens <400> 2 ggcgcaacgc tgagcagctg gcgcgtcccg cgcggccccca gttctgcgca gcttcccgag 60 gctccgcacc agccgcgctt ctgtccgcct gcagggcatt ccagaaagat gaggatattt 120 gctgtcttta tattcatgac ctactggcat ttgctgaacg ccccatacaa caaaatcaac 180 caaagaattt tggttgtgga tccagtcacc tctgaacatg aactgacatg tcaggctgag 240 ggctacccca aggccgaagt catctggaca agcagtgacc atcaagtcct gagtggtaag 300 accaccacca ccaattccaa gagagaggag aagcttttca atgtgaccag cacactgaga 360 atcaacacaa caactaatga gattttctac tgcactttta ggagattaga tcctgaggaa 420 aaccatacag ctgaattggt catcccagaa ctacctctgg cacatcctcc aaatgaaagg 480 actcacttgg taattctggg agccatctta ttatgccttg gtgtagcact gacattcatc 540 ttccgtttaa gaaaagggag aatgatggat gtgaaaaaat gtggcatcca agatacaaac 600 tcaaagaagc aaagtgatac acatttggag gagacgtaat ccagcattgg aacttctgat 660 cttcaagcag ggattctcaa cctgtggttt aggggttcat cggggctgag cgtgacaaga 720 ggaaggaatg ggcccgtggg atgcaggcaa tgtgggactt aaaaggccca agcactgaaa 780 atggaacctg gcgaaagcag aggaggagaa tgaagaaaga tggagtcaaa cagggagcct 840 ggagggagac cttgatactt tcaaatgcct gaggggctca tcgacgcctg tgacagggag 900 aaaggatact tctgaacaag gagcctccaa gcaaatcatc cattgctcat cctaggaaga 960 cgggttgaga atccctaatt tgagggtcag ttcctgcaga agtgcccttt gcctccactc 1020 aatgcctcaa tttgttttct gcatgactga gagtctcagt gttggaacgg gacagtattt 1080 atgtatgagt ttttcctatt tattttgagt ctgtgaggtc ttcttgtcat gtgagtgtgg 1140 ttgtgaatga tttcttttga agatatattg tagtagatgt tacaattttg tcgccaaact 1200 aaacttgctg cttaatgatt tgctcacatc tagtaaaaca tggagtattt gtaaggtgct 1260 tggtctcctc tataactaca agtatacatt ggaagcataa agatcaaacc gttggttgca 1320 taggatgtca cctttattta acccattaat actctggttg acctaatctt attctcagac 1380 ctcaagtgtc tgtgcagtat ctgttccatt taaatatcag ctttacaatt atgtggtagc 1440 ctacacacat aatctcattt catcgctgta accaccctgt tgtgataacc actattattt 1500 tacccatcgt acagctgagg aagcaaacag attaagtaac ttgcccaaac cagtaaatag 1560 cagacctcag actgccaccc actgtccttt tataatacaa tttacagcta tattttactt 1620 taagcaattc ttttattcaa aaaccattta ttaagtgccc ttgcaatatc aatcgctgtg 1680 ccaggcattg aatctacaga tgtgagcaag acaaagtacc tgtcctcaag gagctcatag 1740 tataatgagg agattaacaa gaaaatgtat tattacaatt tagtccagtg tcatagcata 1800 aggatgatgc gaggggaaaa cccgagcagt gttgccaaga gggaggaaata ggccaatgtg 1860 gtctgggacg gttggatata cttaaacatc ttaataatca gagtaatttt catttacaaa 1920 gagaggtcgg tacttaaaat aaccctgaaa aataacactg gaattccttt tctagcatta 1980 tatttattcc tgatttgcct ttgccatata atctaatgct tgtttatata gtgtctggta 2040 ttgtttaaca gttctgtctt ttctatttaa atgccactaa attttaaatt catacctttc 2100 catgattcaa aattcaaaag atcccatggg agatggttgg aaaatctcca cttcatcctc 2160 caagccattc aagtttcctt tccagaagca actgctactg cctttcattc atatgttctt 2220 ctaaagatag tctacatttg gaaatgtatg ttaaaagcac gtatttttaa aatttttttc 2280 ctaaatagta acacattgta tgtctgctgt gtactttgct atttttatattt attttagtgt 2340 ttcttatata gcagatggaa tgaatttgaa gttcccaggg ctgaggatcc atgccttctt 2400 tgtttctaag ttatctttcc catagctttt cattatcttt catatgatcc agtatatgtt 2460 aaatatgtcc tacatataca tttagacaac caccatttgt taagtatttg ctctaggaca 2520 gagtttggat ttgtttatgt ttgctcaaaa ggagacccat gggctctcca gggtgcactg 2580 agtcaatcta gtcctaaaaa gcaatcttat tattaactct gtatgacaga atcatgtctg 2640 gaacttttgt tttctgcttt ctgtcaagta taaacttcac tttgatgctg tacttgcaaa 2700 atcacatttt ctttctggaa attccggcag tgtaccttga ctgctagcta ccctgtgcca 2760 gaaaagcctc attcgttgtg cttgaaccct tgaatgccac cagctgtcat cactacacag 2820 ccctcctaag aggcttcctg gaggtttcga gattcagatg ccctggggaga tcccagagtt 2880 tcctttccct cttggccata ttctggtgtc aatgacaagg agtaccttgg ctttgccaca 2940 tgtcaaggct gaagaaacag tgtctccaac agagctcctt gtgttatctg tttgtacatg 3000 tgcatttgta cagtaattgg tgtgacagtg ttctttgtgt gaattacagg caagaattgt 3060 ggctgagcaa ggcacatagt ctactcagtc tattcctaag tcctaactcc tccttgtggt 3120 gttggatttg taaggcactt tatccctttt gtctcatgtt tcatcgtaaa tggcataggc 3180 agagatgata cctaattctg catttgattg tcactttttg tacctgcatt aatttaataa 3240 aatattctta tttattttgt tacttggtac accagcatgt ccattttctt gtttatttg 3300 tgtttaataa aatgttcagt ttaacatccc agtggagaaa gttaaaaaaa 3349 <210> 3 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 3 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Arg Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Asp Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Leu Pro 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 4 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 4 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Gly Gly Trp Phe Gly Glu Leu Ala Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 5 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 5 Gly Phe Thr Phe Ser Arg Tyr Trp Met Ser 1 5 10 <210> 6 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 6 Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val Lys 1 5 10 15 Gly <210> 7 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 7 Glu Gly Gly Trp Phe Gly Glu Leu Ala Phe Asp Tyr 1 5 10 <210> 8 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 8 Arg Ala Ser Gln Arg Val Ser Ser Ser Tyr Leu Ala 1 5 10 <210> 9 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 9 Asp Ala Ser Ser Arg Ala Thr 1 5 <210> 10 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 10 Gln Gln Tyr Gly Ser Leu Pro Trp Thr 1 5 <210> 11 <211> 139 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 11 Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys 1 5 10 15 Arg Ala Ser Gln Ser Ile Asn Ser Tyr Leu Asp Trp Tyr Gln Gln Lys 20 25 30 Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln 35 40 45 Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 50 55 60 Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 65 70 75 80 Cys Gln Gln Tyr Tyr Ser Thr Pro Phe Thr Phe Gly Pro Gly Thr Lys 85 90 95 Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro 100 105 110 Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu 115 120 125 Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val 130 135 <210> 12 <211> 167 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 12 Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser 1 5 10 15 Gly Phe Thr Phe Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro 20 25 30 Gly Lys Gly Leu Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Ser Asn 35 40 45 Lys Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp 50 55 60 Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu 65 70 75 80 Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Pro Arg Gly Ala Thr Leu 85 90 95 Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val 100 105 110 Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu 130 135 140 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Ala Leu Thr Ser Gly Val His 165 <210> 13 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 13 Gly Phe Thr Phe Ser Ser Tyr Gly Met His 1 5 10 <210> 14 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 14 Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 1 5 10 15 <210> 15 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 15 Asp Pro Arg Gly Ala Thr Leu Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val 1 5 10 15 <210> 16 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 16 Arg Ala Ser Gln Ser Ile Asn Ser Tyr Leu Asp 1 5 10 <210> 17 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 17 Ala Ala Ser Ser Leu Gln Ser 1 5 <210> 18 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 18 Gln Gln Tyr Tyr Ser Thr Pro Phe Thr 1 5

Claims (75)

A method of treating bladder cancer in a subject in need of treatment of bladder cancer, comprising administering to the subject an anti-PD-L1 antibody or antigen-binding fragment thereof at 10 mg/kg to 20 mg/kg every 2 to 4 weeks (Q2W to Q4W) to treat bladder cancer. A method comprising administering in an amount of mg/kg. The method of claim 1, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is durvalumab or an antigen-binding fragment thereof. The method of claim 1 or 2, wherein the bladder cancer is urothelial carcinoma (UC) and/or cancer of bladder-related structures and tissues, including the ureter, urethra, urachus, and/or renal pelvis. The method of claim 3, wherein the bladder cancer is urothelial carcinoma, advanced UC, or metastatic UC. The method of claim 1 , 2, or 4, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is administered to the subject in an amount of 10 mg/kg every two weeks (Q2W). . The method of claim 1 , 2, or 4, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is administered to the subject in an amount of 20 mg/kg every two weeks (Q2W). . The method of claim 1 , 2, or 4, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is administered to the subject in an amount of 10 mg/kg every 3 weeks (Q3W). . The method of claim 1 , 2, or 4, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is administered to the subject in an amount of 20 mg/kg every 3 weeks (Q3W). . The method of claim 1 , 2, or 4, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is administered to the subject in an amount of 10 mg/kg every 4 weeks (Q4W). . The method of claim 1 , 2, or 4, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is administered to the subject in an amount of 20 mg/kg every 4 weeks (Q4W). . The method of claim 5 , wherein the anti-PD-L1 antibody or antigen binding fragment thereof is administered to the subject by intravenous infusion. 12. The method of claim 11, wherein the anti-PD-L1 antibody or antigen binding fragment thereof is administered to the subject over 30 to 90 minutes. 13. The method of claim 12, wherein the anti-PD-L1 antibody or antigen binding fragment thereof is administered to the subject over 60 minutes. The method of claim 5 , wherein the anti-PD-L1 antibody or antigen binding fragment thereof is administered to the subject until the subject achieves an overall survival response, complete response, disease progression, or unacceptable toxicity. The method of claim 1 , 2, or 4, wherein the anti-CTLA4 antibody or antigen binding fragment thereof is co-administered to the subject. 16. The method of claim 15, wherein the anti-CTLA4 antibody is tremelimumab. 17. The method of claim 16, wherein the anti-PD-L1 antibody or antigen binding fragment thereof is administered in an amount of 1500 mg Q4W and tremelimumab is administered in an amount of about 75 mg Q4W. The method of claim 1 , 2 , or 4 , wherein the subject has reduced or low levels of expression of PD-L1 (PD-L1-low), or negligible to low expression of PD-L1. A method wherein a person is identified as having bladder cancer with expression (PD-L1-low/neg). The method of claim 1 , 2 , or 4 , wherein the subject is identified as having bladder cancer with high levels of expression of PD-L1 (PD-L1-high). 19. The method of claim 18, wherein the bladder cancer is PD-L1 low or PD-L1-low/neg when less than 25% of the bladder cancer cells exhibit PD-L1 staining. A method of treating bladder cancer in a subject in need thereof, comprising administering durvalumab or an antigen-binding fragment thereof in an amount of 10 mg/kg Q2W to the subject having bladder cancer to treat bladder cancer. 22. The method of claim 21, wherein the subject's bladder cancer is urothelial carcinoma (UC), advanced UC, or metastatic UC. 23. The method of claim 22, wherein durvalumab is administered by intravenous (IV) infusion. 24. The method of claim 23, wherein the IV infusion occurs over 60 minutes. 23. The method of claim 22, wherein at least 20% of subjects with UC achieve an overall response rate. 23. The method of claim 22, wherein the subject reaches a therapeutic response 1 to 12 months after initial treatment. 23. The method of claim 22, wherein the subject's UC is identified as PD-L1-low or PD-L1 low/neg for PD-L1 expression. 23. The method of claim 22, wherein the subject's UC is identified as PD-L1-high for PD-L1 expression. The method of claim 27 or 28, wherein about 5% of subjects with UC identified as PD-L1-low/neg or PD-L1-high achieve a complete response (CR). 23. The method of claim 21 or 22, wherein the duration of the subject's response to treatment with durvalumab or antigen-binding fragment thereof is for at least 6 months. The method of claim 1 , 2 , or 4 , wherein the subject has previously received primary cancer therapy comprising a platinum drug or a platinum drug in combination with another anticancer agent. 23. The method of claim 21 or 22, wherein the subject has previously received primary cancer therapy comprising a platinum drug or a platinum drug in combination with another anticancer agent. A method of treating a subject with urothelial carcinoma (UC), comprising treating the subject's UC by administering to the subject 10 mg/kg durvalumab every two weeks (Q2W). 34. The method of claim 33, wherein the subject's UC is identified as PD-L1-low or PD-L1-low/neg. 34. The method of claim 33, wherein the subject's UC is identified as PD-L1-high. 36. The method of any one of claims 33-35, wherein administration is by intravenous infusion. 36. The method of any one of claims 33-35, wherein the subject has previously received primary cancer therapy comprising a platinum drug or a platinum drug in combination with another anticancer agent. 34. The method of claim 33, further comprising administering to the subject an effective amount of an anti-CTLA4 antibody or antigen-binding fragment thereof simultaneously with or at a different time from the administration of durvalumab or antigen-binding fragment thereof. A method of treating a subject with bladder cancer whose cancer has progressed following treatment with a platinum drug or a platinum drug in combination with another anticancer agent, comprising: -Administering the PD-L1 antibody or antigen-binding fragment thereof in an amount of 10 mg/kg to 20 mg/kg every 2 to 4 weeks (Q2W to Q4W). 40. The method of claim 39, wherein the primary cancer treatment is a treatment selected from cisplatin, cisplatin and gemcitabine, cisplatin and methotrexate, vinblastine, ADRIAMYCIN ^™ (doxorubicin), or a dual combination of carboplatin and gemcitabine. Including, method. 41. The method of claim 39 or 40, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is durvalumab or an antigen-binding fragment thereof. 42. The method of claim 41, wherein the anti-PD-L1 antibody or antigen binding fragment thereof is administered to the subject in an amount of 10 mg/kg every two weeks (Q2W). 42. The method of claim 41, wherein the anti-PD-L1 antibody or antigen binding fragment thereof is administered to the subject in an amount of 10 mg/kg every 4 weeks (Q4W). 42. The method of claim 41, wherein the anti-PD-L1 antibody or antigen binding fragment thereof is administered to the subject in an amount of 20 mg/kg every two weeks (Q2W). 42. The method of claim 41, wherein the anti-PD-L1 antibody or antigen binding fragment thereof is administered to the subject in an amount of 20 mg/kg every 4 weeks (Q4W). 46. The method of any one of claims 42-45, wherein the anti-PD-L1 antibody or antigen binding fragment thereof is administered to the subject by intravenous infusion. 46. The method of any one of claims 39-45, wherein the bladder cancer is urothelial carcinoma (UC), advanced UC, or metastatic UC. 48. The method of claim 47, wherein the subject's UC is identified as PD-L1-low or PD-L1-low/neg. 48. The method of claim 47, wherein the subject's UC is identified as PD-L1-high. 49. The method of claim 48, wherein the bladder cancer is PD-L1 low or PD-L1-low/neg when less than 25% of the cancer cells exhibit PD-L1 staining. The method of any one of claims 39 to 45, wherein an effective amount of the anti-CTLA4 antibody or antigen-binding fragment thereof is administered to the subject with bladder cancer simultaneously with or at a different time than the administration of the anti-PD-L1 antibody or antigen-binding fragment thereof. Co-administered to a method. 52. The method of claim 51, wherein the anti-CTLA4 antibody or antigen binding fragment thereof is trimelimumab or antigen binding fragment thereof. The method of any one of claims 18 to 20, 27, 28, 34, 35, 48, or 49, wherein PD-L1 is detected using immunohistochemistry. How to become. 54. The method of claim 53, wherein immunohistochemistry is performed on formalin fixed, paraffin embedded cancer cells. The method of claim 1 , 21 , 33, or 39, wherein the treatment results in overall survival, progression free survival, or complete response in the subject. The method of claim 1 , 21 , 33, or 39, wherein the median time to treatment response is about 1 month to 8 months. The method of claim 1 , 21 , 33, or 39, wherein the subject maintains a response for at least 6 to 12 months or longer. The method of claim 1 , 21 , 33, or 39, wherein a treatment response is detected in about 30% of subjects with bladder cancer or high PD-L1 expression on bladder tumors. The method of claim 1 , 21 , 33, or 39, wherein a treatment response is detected in about 8% of subjects with bladder cancer or low/negative PD-L1 expression on bladder tumors. . A method of treating bladder cancer in a subject in need of treatment for bladder cancer, comprising administering trimelimumab or an antigen-binding fragment thereof in an amount of 50 to 150 mg every 2 to 4 weeks to the subject having bladder cancer to treat bladder cancer. A method comprising administering durvalumab or an antigen-binding fragment thereof to the subject in an amount of 50 to 2000 mg every 2 to 4 weeks (Q2W to Q4W). The method of claim 60, wherein durvalumab or its antigen-binding fragment is administered in an amount of 1500 mg every 4 weeks (Q4W), and tremelimumab or its antigen-binding fragment is administered in an amount of 75 mg every 4 weeks (Q4W). How to become. 62. The method of claim 60 or 61, wherein durvalumab and tremelimumab or antigen binding fragments thereof are administered up to 4 doses per cycle. 63. The method of any one of claims 60-62, wherein durvalumab and tremelimumab or their antigen-binding fragments are administered simultaneously or at different times. 61. The method of claim 60, wherein the subject has bladder cancer with reduced or low levels of expression of PD-L1 (PD-L1-low), or negligible to low expression of PD-L1 (PD-L1-low/neg). A method that is confirmed to have a . 61. The method of claim 60, wherein the subject is identified as having bladder cancer with high levels of expression of PD-L1 (PD-L1-high). 66. The method of any one of claims 60-65, wherein the bladder cancer is urothelial carcinoma (UC) and/or cancer of bladder-related structures and tissues, including the ureter, urethra, urachus, and/or renal pelvis. 66. The method of any one of claims 60-65, wherein the bladder cancer is urothelial carcinoma, advanced UC, or metastatic UC. The method of claim 19 , 28 , 35 , 49 , or 65 , wherein greater than 65% of treated subjects with bladder cancer identified as PD-L1-high at 6 months Method having an overall survival response. The method of claim 19 , 28 , 35 , 49 , or 65 , wherein about 65% of treated subjects with bladder cancer identified as PD-L1-high have bladder cancer at 9 months. Method having an overall survival response. The method of claim 19 , 28 , 35 , 49 , or 65 , wherein about 60% of treated subjects with bladder cancer identified as PD-L1-high at 12 months Method having an overall survival response. The method of any one of claims 18, 27, 34, 48, or 64, wherein greater than 40% of treated subjects have bladder cancer confirmed as PD-L1-low/neg. Methods, showing overall survival response at months. The method of any one of claims 18, 27, 34, 48, or 64, wherein more than 35% of treated subjects have bladder cancer confirmed as PD-L1-low/neg. Methods, showing overall survival response at months and 12 months. The method of claim 1 , 21 , 33, or 39, wherein about 60% of treated subjects demonstrate an overall survival response at 6 months. The method of claim 1 , 21 , 33, or 39, wherein greater than 55% of treated subjects demonstrate an overall survival response at 9 months. The method of claim 1 , 21 , 33, or 39, wherein greater than 50% of treated subjects demonstrate an overall survival response at 12 months.